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[[File:Homologous recombinational repair of DNA double-strand damage.jpg|thumb|300px|'''Recombinational repair of DNA double-strand damage - some key steps.'''  [[Ataxia telangiectasia mutated|ATM]] (ATM) is a [[protein kinase]] that is recruited and activated by [[DNA repair#Double-strand breaks|DNA double-strand breaks]].  DNA double-strand damages also activate the [[FANC proteins|Fanconi anemia core complex]] (FANCA/B/C/E/F/G/L/M).<ref name=Andrea>{{cite journal |vauthors=D'Andrea AD |title=Susceptibility pathways in Fanconi's anemia and breast cancer |journal=N. Engl. J. Med. |volume=362 |issue=20 |pages=1909–19 |year=2010 |pmid=20484397 |pmc=3069698 |doi=10.1056/NEJMra0809889 |url=}}</ref>  The FA core complex [[ubiquitin|monoubiquitinates]] the downstream targets FANCD2 and FANCI.<ref name="pmid19633289">{{cite journal |vauthors=Sobeck A, Stone S, Landais I, de Graaf B, Hoatlin ME |title=The Fanconi anemia protein FANCM is controlled by FANCD2 and the ATR/ATM pathways |journal=J. Biol. Chem. |volume=284 |issue=38 |pages=25560–8 |year=2009 |pmid=19633289 |pmc=2757957 |doi=10.1074/jbc.M109.007690 |url=}}</ref>  ATM activates (phosphorylates) [[CHEK2]] and [[FANCD2]]<ref name=Castillo>{{cite journal |vauthors=Castillo P, Bogliolo M, Surralles J |title=Coordinated action of the Fanconi anemia and ataxia telangiectasia pathways in response to oxidative damage |journal=DNA Repair (Amst.) |volume=10 |issue=5 |pages=518–25 |year=2011 |pmid=21466974 |doi=10.1016/j.dnarep.2011.02.007 |url=}}</ref>  CHEK2 phosphorylates BRCA1.<ref name="pmid21088254">{{cite journal |vauthors=Stolz A, Ertych N, Bastians H |title=Tumor suppressor CHK2: regulator of DNA damage response and mediator of chromosomal stability |journal=Clin. Cancer Res. |volume=17 |issue=3 |pages=401–5 |year=2011 |pmid=21088254 |doi=10.1158/1078-0432.CCR-10-1215 |url=}}</ref>  Ubiquinated FANCD2 complexes with [[BRCA1]] and [[RAD51]].<ref name="pmid12239151">{{cite journal |vauthors=Taniguchi T, Garcia-Higuera I, Andreassen PR, Gregory RC, Grompe M, D'Andrea AD |title=S-phase-specific interaction of the Fanconi anemia protein, FANCD2, with BRCA1 and RAD51 |journal=Blood |volume=100 |issue=7 |pages=2414–20 |year=2002 |pmid=12239151 |doi=10.1182/blood-2002-01-0278 |url=}}</ref>  The PALB2 protein acts as a hub,<ref name="pmid24998779">{{cite journal |vauthors=Park JY, Zhang F, Andreassen PR |title=PALB2: the hub of a network of tumor suppressors involved in DNA damage responses |journal=Biochim. Biophys. Acta |volume=1846 |issue=1 |pages=263–75 |year=2014 |pmid=24998779 |pmc=4183126 |doi=10.1016/j.bbcan.2014.06.003 |url=}}</ref> bringing together BRCA1, BRCA2 and RAD51 at the site of a DNA double-strand break, and also binds to RAD51C, a member of the RAD51 paralog complex [[RAD51L1|RAD51B]]-[[RAD51C]]-[[RAD51L3|RAD51D]]-[[XRCC2]] (BCDX2).  The BCDX2 complex is responsible for RAD51 recruitment or stabilization at damage sites.<ref name=Chun>{{cite journal |vauthors=Chun J, Buechelmaier ES, Powell SN |title=Rad51 paralog complexes BCDX2 and CX3 act at different stages in the BRCA1-BRCA2-dependent homologous recombination pathway |journal=Mol. Cell. Biol. |volume=33 |issue=2 |pages=387–95 |year=2013 |pmid=23149936 |pmc=3554112 |doi=10.1128/MCB.00465-12 |url=}}</ref>  [[RAD51]] plays a major role in [[homologous recombination]]al repair of DNA during double strand break repair. In this process, an ATP dependent DNA strand exchange takes place in which a single strand invades base-paired strands of homologous DNA molecules.  RAD51 is involved in the search for homology and strand pairing stages of the process.]]
[[File:Homologous recombinational repair of DNA double-strand damage.jpg|thumb|300px|'''Recombinational repair of DNA double-strand damage - some key steps.'''  [[Ataxia telangiectasia mutated|ATM]] (ATM) is a [[protein kinase]] that is recruited and activated by [[DNA repair#Double-strand breaks|DNA double-strand breaks]].  DNA double-strand damages also activate the [[FANC proteins|Fanconi anemia core complex]] (FANCA/B/C/E/F/G/L/M).<ref name=Andrea>{{cite journal |vauthors=D'Andrea AD |title=Susceptibility pathways in Fanconi's anemia and breast cancer |journal=N. Engl. J. Med. |volume=362 |issue=20 |pages=1909–19 |year=2010 |pmid=20484397 |pmc=3069698 |doi=10.1056/NEJMra0809889 |url=}}</ref>  The FA core complex [[ubiquitin|monoubiquitinates]] the downstream targets FANCD2 and FANCI.<ref name="pmid19633289">{{cite journal |vauthors=Sobeck A, Stone S, Landais I, de Graaf B, Hoatlin ME |title=The Fanconi anemia protein FANCM is controlled by FANCD2 and the ATR/ATM pathways |journal=J. Biol. Chem. |volume=284 |issue=38 |pages=25560–8 |year=2009 |pmid=19633289 |pmc=2757957 |doi=10.1074/jbc.M109.007690 |url=}}</ref>  ATM activates (phosphorylates) [[CHEK2]] and [[FANCD2]]<ref name=Castillo>{{cite journal |vauthors=Castillo P, Bogliolo M, Surralles J |title=Coordinated action of the Fanconi anemia and ataxia telangiectasia pathways in response to oxidative damage |journal=DNA Repair (Amst.) |volume=10 |issue=5 |pages=518–25 |year=2011 |pmid=21466974 |doi=10.1016/j.dnarep.2011.02.007 |url=}}</ref>  CHEK2 phosphorylates BRCA1.<ref name="pmid21088254">{{cite journal |vauthors=Stolz A, Ertych N, Bastians H |title=Tumor suppressor CHK2: regulator of DNA damage response and mediator of chromosomal stability |journal=Clin. Cancer Res. |volume=17 |issue=3 |pages=401–5 |year=2011 |pmid=21088254 |doi=10.1158/1078-0432.CCR-10-1215 |url=}}</ref>  Ubiquinated FANCD2 complexes with [[BRCA1]] and [[RAD51]].<ref name="pmid12239151">{{cite journal |vauthors=Taniguchi T, Garcia-Higuera I, Andreassen PR, Gregory RC, Grompe M, D'Andrea AD |title=S-phase-specific interaction of the Fanconi anemia protein, FANCD2, with BRCA1 and RAD51 |journal=Blood |volume=100 |issue=7 |pages=2414–20 |year=2002 |pmid=12239151 |doi=10.1182/blood-2002-01-0278 |url=}}</ref>  The PALB2 protein acts as a hub,<ref name="pmid24998779">{{cite journal |vauthors=Park JY, Zhang F, Andreassen PR |title=PALB2: the hub of a network of tumor suppressors involved in DNA damage responses |journal=Biochim. Biophys. Acta |volume=1846 |issue=1 |pages=263–75 |year=2014 |pmid=24998779 |pmc=4183126 |doi=10.1016/j.bbcan.2014.06.003 |url=}}</ref> bringing together BRCA1, BRCA2 and RAD51 at the site of a DNA double-strand break, and also binds to RAD51C, a member of the RAD51 paralog complex [[RAD51L1|RAD51B]]-[[RAD51C]]-[[RAD51L3|RAD51D]]-[[XRCC2]] (BCDX2).  The BCDX2 complex is responsible for RAD51 recruitment or stabilization at damage sites.<ref name=Chun>{{cite journal |vauthors=Chun J, Buechelmaier ES, Powell SN |title=Rad51 paralog complexes BCDX2 and CX3 act at different stages in the BRCA1-BRCA2-dependent homologous recombination pathway |journal=Mol. Cell. Biol. |volume=33 |issue=2 |pages=387–95 |year=2013 |pmid=23149936 |pmc=3554112 |doi=10.1128/MCB.00465-12 |url=}}</ref>  [[RAD51]] plays a major role in [[homologous recombination]]al repair of DNA during double strand break repair. In this process, an ATP dependent DNA strand exchange takes place in which a single strand invades base-paired strands of homologous DNA molecules.  RAD51 is involved in the search for homology and strand pairing stages of the process.]]


The clinical phenotype of mutational defects in all [[Fanconi anemia]] (FA) complementation groups is similar.  This phenotype is characterized by progressive bone marrow failure, cancer proneness and typical birth defects<ref>{{Cite journal|last=Walden|first=Helen|last2=Deans|first2=Andrew J.|date=2014|title=The Fanconi anemia DNA repair pathway: structural and functional insights into a complex disorder|url=https://www.ncbi.nlm.nih.gov/pubmed/24773018|journal=Annual Review of Biophysics|volume=43|pages=257–278|doi=10.1146/annurev-biophys-051013-022737|issn=1936-1238|pmid=24773018}}</ref>. The main cellular phenotype is hypersensitivity to DNA damage, particularly [[Crosslinking of DNA|inter-strand DNA crosslinks]].<ref>{{Cite journal|last=Deans|first=Andrew J.|last2=West|first2=Stephen C.|date=2011-06-24|title=DNA interstrand crosslink repair and cancer|url=https://www.ncbi.nlm.nih.gov/pubmed/21701511|journal=Nature Reviews. Cancer|volume=11|issue=7|pages=467–480|doi=10.1038/nrc3088|issn=1474-1768|pmc=3560328|pmid=21701511}}</ref>  The FA proteins interact through a multi-protein pathway.  DNA interstrand crosslinks are highly deleterious damages that are repaired by [[homologous recombination]] involving coordination of FA proteins and ''breast cancer susceptibility gene 1 ([[BRCA1]])''.
The clinical phenotype of mutational defects in all [[Fanconi anemia]] (FA) complementation groups is similar.  This phenotype is characterized by progressive bone marrow failure, cancer proneness and typical birth defects.<ref>{{Cite journal|last=Walden|first=Helen|last2=Deans|first2=Andrew J.|date=2014|title=The Fanconi anemia DNA repair pathway: structural and functional insights into a complex disorder|journal=Annual Review of Biophysics|volume=43|pages=257–278|doi=10.1146/annurev-biophys-051013-022737|issn=1936-1238|pmid=24773018}}</ref>  The main cellular phenotype is hypersensitivity to DNA damage, particularly [[Crosslinking of DNA|inter-strand DNA crosslinks]].<ref>{{Cite journal|last=Deans|first=Andrew J.|last2=West|first2=Stephen C.|date=2011-06-24|title=DNA interstrand crosslink repair and cancer|journal=Nature Reviews. Cancer|volume=11|issue=7|pages=467–480|doi=10.1038/nrc3088|issn=1474-1768|pmc=3560328|pmid=21701511}}</ref>  The FA proteins interact through a multi-protein pathway.  DNA interstrand crosslinks are highly deleterious damages that are repaired by [[homologous recombination]] involving coordination of FA proteins and ''breast cancer susceptibility gene 1 ([[BRCA1]])''.


The Fanconi Anemia (FA) DNA repair pathway is essential for the recognition and repair of DNA interstrand crosslinks (ICL).  A critical step in the pathway is the monoubiquitination of [[FANCD2]] by the RING E3 ligase FANCL. FANCL comprises 3 domains, a [[RING finger domain|RING]] domain that interacts with E2 conjugating enzymes, a central domain required for substrate interaction, and an N-terminal E2-like fold (ELF) domain that interacts with [[FANCB]]<ref>{{Cite journal|last=van Twest|first=Sylvie|last2=Murphy|first2=Vincent J.|last3=Hodson|first3=Charlotte|last4=Tan|first4=Winnie|last5=Swuec|first5=Paolo|last6=O'Rourke|first6=Julienne J.|last7=Heierhorst|first7=Jörg|last8=Crismani|first8=Wayne|last9=Deans|first9=Andrew J.|date=2017-01-19|title=Mechanism of Ubiquitination and Deubiquitination in the Fanconi Anemia Pathway|url=https://www.ncbi.nlm.nih.gov/pubmed/27986371|journal=Molecular Cell|volume=65|issue=2|pages=247–259|doi=10.1016/j.molcel.2016.11.005|issn=1097-4164|pmid=27986371}}</ref>. The ELF domain of FANCL is also required to mediate a non-covalent interaction
The Fanconi Anemia (FA) DNA repair pathway is essential for the recognition and repair of DNA interstrand crosslinks (ICL).  A critical step in the pathway is the monoubiquitination of [[FANCD2]] by the RING E3 ligase FANCL. FANCL comprises 3 domains, a [[RING finger domain|RING]] domain that interacts with E2 conjugating enzymes, a central domain required for substrate interaction, and an N-terminal E2-like fold (ELF) domain that interacts with [[FANCB]].<ref>{{Cite journal|last=van Twest|first=Sylvie|last2=Murphy|first2=Vincent J.|last3=Hodson|first3=Charlotte|last4=Tan|first4=Winnie|last5=Swuec|first5=Paolo|last6=O'Rourke|first6=Julienne J.|last7=Heierhorst|first7=Jörg|last8=Crismani|first8=Wayne|last9=Deans|first9=Andrew J.|date=2017-01-19|title=Mechanism of Ubiquitination and Deubiquitination in the Fanconi Anemia Pathway|journal=Molecular Cell|volume=65|issue=2|pages=247–259|doi=10.1016/j.molcel.2016.11.005|issn=1097-4164|pmid=27986371}}</ref> The ELF domain of FANCL is also required to mediate a non-covalent interaction
between FANCL and [[ubiquitin]]. The ELF domain is required to promote efficient DNA damage-induced FANCD2 monoubiquitination in vertebrate cells, suggesting an important function of FANCB and ubiquitin binding by FANCL in vivo.<ref name="pmid26149689">{{cite journal |vauthors=Miles JA, Frost MG, Carroll E, Rowe ML, Howard MJ, Sidhu A, Chaugule VK, Alpi AF, Walden H |title=The Fanconi Anemia DNA Repair Pathway Is Regulated by an Interaction between Ubiquitin and the E2-like Fold Domain of FANCL |journal=J. Biol. Chem. |volume=290 |issue=34 |pages=20995–1006 |year=2015 |pmid=26149689 |pmc=4543658 |doi=10.1074/jbc.M115.675835 |url=}}</ref>
between FANCL and [[ubiquitin]]. The ELF domain is required to promote efficient DNA damage-induced FANCD2 monoubiquitination in vertebrate cells, suggesting an important function of FANCB and ubiquitin binding by FANCL in vivo.<ref name="pmid26149689">{{cite journal |vauthors=Miles JA, Frost MG, Carroll E, Rowe ML, Howard MJ, Sidhu A, Chaugule VK, Alpi AF, Walden H |title=The Fanconi Anemia DNA Repair Pathway Is Regulated by an Interaction between Ubiquitin and the E2-like Fold Domain of FANCL |journal=J. Biol. Chem. |volume=290 |issue=34 |pages=20995–1006 |year=2015 |pmid=26149689 |pmc=4543658 |doi=10.1074/jbc.M115.675835 |url=}}</ref>


Latest revision as of 13:59, 26 June 2018

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Identifiers
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External IDsGeneCards: [1]
Orthologs
SpeciesHumanMouse
Entrez

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Ensembl

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UniProt

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RefSeq (mRNA)

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RefSeq (protein)

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E3 ubiquitin-protein ligase FANCL is an enzyme that in humans is encoded by the FANCL gene.[1]


Function

File:Homologous recombinational repair of DNA double-strand damage.jpg
Recombinational repair of DNA double-strand damage - some key steps. ATM (ATM) is a protein kinase that is recruited and activated by DNA double-strand breaks. DNA double-strand damages also activate the Fanconi anemia core complex (FANCA/B/C/E/F/G/L/M).[2] The FA core complex monoubiquitinates the downstream targets FANCD2 and FANCI.[3] ATM activates (phosphorylates) CHEK2 and FANCD2[4] CHEK2 phosphorylates BRCA1.[5] Ubiquinated FANCD2 complexes with BRCA1 and RAD51.[6] The PALB2 protein acts as a hub,[7] bringing together BRCA1, BRCA2 and RAD51 at the site of a DNA double-strand break, and also binds to RAD51C, a member of the RAD51 paralog complex RAD51B-RAD51C-RAD51D-XRCC2 (BCDX2). The BCDX2 complex is responsible for RAD51 recruitment or stabilization at damage sites.[8] RAD51 plays a major role in homologous recombinational repair of DNA during double strand break repair. In this process, an ATP dependent DNA strand exchange takes place in which a single strand invades base-paired strands of homologous DNA molecules. RAD51 is involved in the search for homology and strand pairing stages of the process.

The clinical phenotype of mutational defects in all Fanconi anemia (FA) complementation groups is similar. This phenotype is characterized by progressive bone marrow failure, cancer proneness and typical birth defects.[9] The main cellular phenotype is hypersensitivity to DNA damage, particularly inter-strand DNA crosslinks.[10] The FA proteins interact through a multi-protein pathway. DNA interstrand crosslinks are highly deleterious damages that are repaired by homologous recombination involving coordination of FA proteins and breast cancer susceptibility gene 1 (BRCA1).

The Fanconi Anemia (FA) DNA repair pathway is essential for the recognition and repair of DNA interstrand crosslinks (ICL). A critical step in the pathway is the monoubiquitination of FANCD2 by the RING E3 ligase FANCL. FANCL comprises 3 domains, a RING domain that interacts with E2 conjugating enzymes, a central domain required for substrate interaction, and an N-terminal E2-like fold (ELF) domain that interacts with FANCB.[11] The ELF domain of FANCL is also required to mediate a non-covalent interaction between FANCL and ubiquitin. The ELF domain is required to promote efficient DNA damage-induced FANCD2 monoubiquitination in vertebrate cells, suggesting an important function of FANCB and ubiquitin binding by FANCL in vivo.[12]

A nuclear complex containing FANCL (as well as FANCA, FANCB, FANCC, FANCE, FANCF, FANCG and FANCM) is essential for the activation of the FANCD2 protein to the mono-ubiquitinated isoform.[2] In normal, non-mutant, cells FANCD2 is mono-ubiquinated in response to DNA damage. Activated FANCD2 protein co-localizes with BRCA1 (breast cancer susceptibility protein) at ionizing radiation-induced foci and in synaptonemal complexes of meiotic chromosomes (see Figure: Recombinational repair of double strand damage).

References

  1. ↑ "Entrez Gene: FANCL Fanconi anemia, complementation group L".
  2. ↑ 2.0 2.1 D'Andrea AD (2010). "Susceptibility pathways in Fanconi's anemia and breast cancer". N. Engl. J. Med. 362 (20): 1909–19. doi:10.1056/NEJMra0809889. PMC 3069698. PMID 20484397.
  3. ↑ Sobeck A, Stone S, Landais I, de Graaf B, Hoatlin ME (2009). "The Fanconi anemia protein FANCM is controlled by FANCD2 and the ATR/ATM pathways". J. Biol. Chem. 284 (38): 25560–8. doi:10.1074/jbc.M109.007690. PMC 2757957. PMID 19633289.
  4. ↑ Castillo P, Bogliolo M, Surralles J (2011). "Coordinated action of the Fanconi anemia and ataxia telangiectasia pathways in response to oxidative damage". DNA Repair (Amst.). 10 (5): 518–25. doi:10.1016/j.dnarep.2011.02.007. PMID 21466974.
  5. ↑ Stolz A, Ertych N, Bastians H (2011). "Tumor suppressor CHK2: regulator of DNA damage response and mediator of chromosomal stability". Clin. Cancer Res. 17 (3): 401–5. doi:10.1158/1078-0432.CCR-10-1215. PMID 21088254.
  6. ↑ Taniguchi T, Garcia-Higuera I, Andreassen PR, Gregory RC, Grompe M, D'Andrea AD (2002). "S-phase-specific interaction of the Fanconi anemia protein, FANCD2, with BRCA1 and RAD51". Blood. 100 (7): 2414–20. doi:10.1182/blood-2002-01-0278. PMID 12239151.
  7. ↑ Park JY, Zhang F, Andreassen PR (2014). "PALB2: the hub of a network of tumor suppressors involved in DNA damage responses". Biochim. Biophys. Acta. 1846 (1): 263–75. doi:10.1016/j.bbcan.2014.06.003. PMC 4183126. PMID 24998779.
  8. ↑ Chun J, Buechelmaier ES, Powell SN (2013). "Rad51 paralog complexes BCDX2 and CX3 act at different stages in the BRCA1-BRCA2-dependent homologous recombination pathway". Mol. Cell. Biol. 33 (2): 387–95. doi:10.1128/MCB.00465-12. PMC 3554112. PMID 23149936.
  9. ↑ Walden, Helen; Deans, Andrew J. (2014). "The Fanconi anemia DNA repair pathway: structural and functional insights into a complex disorder". Annual Review of Biophysics. 43: 257–278. doi:10.1146/annurev-biophys-051013-022737. ISSN 1936-1238. PMID 24773018.
  10. ↑ Deans, Andrew J.; West, Stephen C. (2011-06-24). "DNA interstrand crosslink repair and cancer". Nature Reviews. Cancer. 11 (7): 467–480. doi:10.1038/nrc3088. ISSN 1474-1768. PMC 3560328. PMID 21701511.
  11. ↑ van Twest, Sylvie; Murphy, Vincent J.; Hodson, Charlotte; Tan, Winnie; Swuec, Paolo; O'Rourke, Julienne J.; Heierhorst, Jörg; Crismani, Wayne; Deans, Andrew J. (2017-01-19). "Mechanism of Ubiquitination and Deubiquitination in the Fanconi Anemia Pathway". Molecular Cell. 65 (2): 247–259. doi:10.1016/j.molcel.2016.11.005. ISSN 1097-4164. PMID 27986371.
  12. ↑ Miles JA, Frost MG, Carroll E, Rowe ML, Howard MJ, Sidhu A, Chaugule VK, Alpi AF, Walden H (2015). "The Fanconi Anemia DNA Repair Pathway Is Regulated by an Interaction between Ubiquitin and the E2-like Fold Domain of FANCL". J. Biol. Chem. 290 (34): 20995–1006. doi:10.1074/jbc.M115.675835. PMC 4543658. PMID 26149689.

Further reading


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