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PMID: 20603073 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, N.I.H., Intramural Research Support, Non-U.S. Gov't

A genetic screen identifies FAN1, a Fanconi anemia-associated nuclease necessary for DNA interstrand crosslink repair.

Molecular cell ·Vol. 39 ·No. 1 ·2010-07-09 ·Pages 36-47

Smogorzewska A, Desetty R, Saito TT, Schlabach M, Lach FP, Sowa ME, Clark AB, Kunkel TA, Harper JW, Colaiácovo MP, Elledge SJ

Abstract

The Fanconi anemia (FA) pathway is responsible for interstrand crosslink repair. At the heart of this pathway is the FANCI-FAND2 (ID) complex, which, upon ubiquitination by the FA core complex, travels to sites of damage to coordinate repair that includes nucleolytic modification of the DNA surrounding the lesion and translesion synthesis. How the ID complex regulates these events is unknown. Here we describe a shRNA screen that led to the identification of two nucleases necessary for crosslink repair, FAN1 (KIAA1018) and EXDL2. FAN1 colocalizes at sites of DNA damage with the ID complex in a manner dependent on FAN1's ubiquitin-binding domain (UBZ), the ID complex, and monoubiquitination of FANCD2. FAN1 possesses intrinsic 5'-3' exonuclease activity and endonuclease activity that cleaves nicked and branched structures. We propose that FAN1 is a repair nuclease that is recruited to sites of crosslink damage in part through binding the ubiquitinated ID complex through its UBZ domain.

MeSH Terms
Amino Acid Sequence Animals Caenorhabditis elegans/metabolism Cell Line Cross-Linking Reagents/metabolism DNA Damage DNA Mismatch Repair/drug effects DNA Repair/drug effects Endodeoxyribonucleases Endonucleases/metabolism Exodeoxyribonucleases/chemistry,metabolism Exonucleases/chemistry,metabolism Fanconi Anemia/enzymology,pathology Fanconi Anemia Complementation Group D2 Protein/metabolism Genetic Testing/methods Genome, Human/genetics Humans Mitomycin/pharmacology Molecular Sequence Data Multifunctional Enzymes Protein Binding/drug effects Protein Structure, Tertiary Protein Transport/drug effects RNA, Small Interfering/metabolism
Chemicals
Cross-Linking Reagents Fanconi Anemia Complementation Group D2 Protein Multifunctional Enzymes RNA, Small Interfering Mitomycin Endodeoxyribonucleases Endonucleases Exodeoxyribonucleases Exonucleases FAN1 protein, human
Authors & Affiliations
11 authors, click to expand affiliations / ORCID
Smogorzewska Agata
Howard Hughes Medical Institute, Department of Genetics, Harvard Medical School, and Brigham and Women's Hospital, Boston, MA 02115, USA. [email protected]
Desetty Rohini
Saito Takamune T
Schlabach Michael
Lach Francis P
Sowa Mathew E
Clark Alan B
Kunkel Thomas A
Harper J Wade
Colaiácovo Monica P
Elledge Stephen J
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Article Info
Journal
Molecular cell
Abbr.
Mol Cell
ISSN
1097-4164
DOI
10.1016/j.molcel.2010.06.023
Email
[email protected]
Published
2010-07-09
Pages
36-47
Language
English
Region
United States
NLM ID
9802571
PMCID
PMC2919743
Subset
IM
Grants
NCI NIH HHS · T32CA09216 · United States
PHS HHS · 1U19A1067751-01 · United States
Howard Hughes Medical Institute · United States
NIGMS NIH HHS · R01 GM072551 · United States
NIGMS NIH HHS · R37 GM044664-23 · United States
NIGMS NIH HHS · R01GM072551 · United States
Intramural NIH HHS · Z01 ES065089 · United States
NIGMS NIH HHS · R37 GM044664 · United States
NIGMS NIH HHS · R01 GM054137 · United States
NCI NIH HHS · T32 CA009216 · United States
NIA NIH HHS · R01 AG011085 · United States
Corrections
CommentIn
PMID: 20670886
CommentIn
PMID: 20700143
External Links
PubMed source DOI: 10.1016/j.molcel.2010.06.023 PMC Full Text View journal details
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