Crosstalk between BRCA-Fanconi anemia and mismatch repair pathways prevents MSH2-dependent aberrant DNA damage responses
Peng, Min ; Xie, Jenny X. ; Ucher, Anna J. ; Stavnezer, Janet ; Cantor, Sharon B.
Citations
Student Authors
Faculty Advisor
Academic Program
UMass Chan Affiliations
Document Type
Publication Date
Keywords
Animals
BRCA1 Protein
Basic-Leucine Zipper Transcription Factors
Cell Line
Chromosome Aberrations
*DNA Damage
*DNA Mismatch Repair
DNA Replication
DNA-Binding Proteins
Fanconi Anemia Complementation Group A Protein
Fanconi Anemia Complementation Group D2 Protein
Fanconi Anemia Complementation Group Proteins
Humans
Mice
Mice, Mutant Strains
Mitomycin
MutS Homolog 2 Protein
Nuclear Proteins
Fanconi anemia
FANCJ
mismatch repair
MLH1
replication stress
Biochemistry
Cancer Biology
Genetics
Molecular Genetics
Neoplasms
Subject Area
Embargo Expiration Date
Abstract
Several proteins in the BRCA-Fanconi anemia (FA) pathway, such as FANCJ, BRCA1, and FANCD2, interact with mismatch repair (MMR) pathway factors, but the significance of this link remains unknown. Unlike the BRCA-FA pathway, the MMR pathway is not essential for cells to survive toxic DNA interstrand crosslinks (ICLs), although MMR proteins bind ICLs and other DNA structures that form at stalled replication forks. We hypothesized that MMR proteins corrupt ICL repair in cells that lack crosstalk between BRCA-FA and MMR pathways. Here, we show that ICL sensitivity of cells lacking the interaction between FANCJ and the MMR protein MLH1 is suppressed by depletion of the upstream mismatch recognition factor MSH2. MSH2 depletion suppresses an aberrant DNA damage response, restores cell cycle progression, and promotes ICL resistance through a Rad18-dependent mechanism. MSH2 depletion also suppresses ICL sensitivity in cells deficient for BRCA1 or FANCD2, but not FANCA. Rescue by Msh2 loss was confirmed in Fancd2-null primary mouse cells. Thus, we propose that regulation of MSH2-dependent DNA damage response underlies the importance of interactions between BRCA-FA and MMR pathways.
Source
EMBO J. 2014 Aug 1;33(15):1698-712. doi: 10.15252/embj.201387530. Epub 2014 Jun 25. Link to article on publisher's site