Crosstalk between BRCA‐Fanconi anemia and mismatch repair pathways prevents MSH2‐dependent aberrant DNA damage responses

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.

What is wrong with Fanconi anemia cells?

“…[27][28][29] We found that the MMR protein, MSH2 underlies the ICL processing defects resulting from loss of the FANCJ-MLH1 interaction. 19 Consistent with this finding, depletion of MSH2 suppresses defects found in cells deficient for the FANCJ-MLH1 interaction, including ICL -induced sensitivity, chromosomal aberrations, abnormal G2/M accumulation, and as well as an over-active NHEJ pathway. Depletion of MSH2 did not appear to alter recombination.…”

“…18 Likewise loss of NHEJ did not enhance ICL resistance in worms or human FA-J patient cells that are deficient for the BRCA1-interacting helicase FANCJ (BACH1/BRIP1). 13,19 The relationship between FA and NHEJ pathways appears to be species-specific given that in contrast to the rescue in human cells, 13 inactivation of NHEJ exacerbated ICL sensitivity in Fancd2-¡/¡ mouse cells and double knockout mice had more severe developmental defects. 18,20 Thus, BRCA-FA proteins likely have several functions in the repair of ICLs that extend beyond balancing HR and NHEJ pathways.…”

“…Instead, the restored ICL resistance was dependent on Rad18-dependent pathway and the Rev1 bypass polymerase suggesting MSH2 depletion enhanced TLS. 19 These outcomes are not unprecedented. In fact, MSH2 deficiency reverses proliferation defects due to short telomeres by a mechanism independent of recombination.…”

“…34,[37][38][39][40] Our data indicate that at stalled replication forks, MSH2 interferes with replication restart in cells lacking the FANCJ-MLH1 interaction. 19 Therefore, the interaction between FANCJ and MLH1 could serve to coordinate the DDR and to prevent unproductive MMR processing that impedes the recovery of cells following replication stress.…”

Screening for mutations in two exons of FANCG gene in Pakistani population

“…After completion of DNA repair, it is inactivated again. FA pathway is often restricted to S-phase of the cell cycle 16 . FANCG (OMIM # 602956) previously known as XRCC9, was first identified in Chinese hamster ovary (CHO) mutant UV40 cell line 17 .…”