Human MutS and FANCM complexes function as redundant DNA damage sensors in the Fanconi Anemia pathway

Min Huang, Richard Kennedy, Abdullah M. Ali, Lisa A. Moreau, Amom Ruhikanta Meetei, Alan D. D'Andrea, Clark C. Chen

Research output: Contribution to journalArticlepeer-review

20 Scopus citations


The Fanconi Anemia (FA) pathway encodes a DNA damage response activated by DNA damage-stalled replication forks. Current evidence suggests that the FA pathway initiates with DNA damage recognition by the FANCM complex (FANCM/FAAP24/MHF). However, genetic inactivation of FANCM in mouse and DT40 cells causes only a partial defect in the FA pathway activation, suggesting the existence of redundant DNA damage sensors. Here we show that the MutS homologs function in this capacity. A RNAi screen revealed that MSH2 silencing caused defective FA pathway activation, as assessed by damage-induced FANCD2 mono-ubiquitination. A similar FA pathway defect was observed with MSH3 or MSH6 silencing. MSH2 depletion caused cellular phenotypes associated with defective FA pathway, including mitomycin C hypersensitivity and chromosomal instability. Further, silencing of FANCM in MSH2 deficient HEC59 cells caused a more severe FA defect relative to comparable silencing in MSH2 complemented HEC59. +. Chr2 cells, suggesting redundant functions between MSH2 and FANCM. Consistent with this hypothesis, depletion of MSH2 resulted in defective chromatin localization of the FA core complex upon DNA damage. Further, MSH2 was co-purified and co-immunoprecipitated with FA core complex components. Taken together, our results suggest that human MutS homologs and FANCM complexes function as redundant DNA damage sensors of the FA pathway.

Original languageEnglish (US)
Pages (from-to)1203-1212
Number of pages10
JournalDNA Repair
Issue number12
StatePublished - Dec 10 2011

Bibliographical note

Funding Information:
We thank Dr. Thomas A. Kunkel for kindly providing the HEC59 and HEC59 + Chr2 cells. We thank Dr. Thiyam Ramsing Singh for the reagents and Dr. Pascal Zinn for his assistance with the clonogenic assays. We thank Jung Min Kim, George-Lucian Moldovan, Younghoon Kee, Eunmi Park and Donniphat Dejsuphong for critical reading of this manuscript. This work was supported by National Institutes of Health Grants RO1HL52725 , RO1DK43889 , PO1150654 , P50CA105009-01 , PO1HL54785 (A.D.), a grant from the Leukemia/Lymphoma Society LLS2007 (A.D.), the Doris Duke Charitable Foundation Clinical Scientist Development Award (C.C.C.), the Sontag Foundation Distinguished Scientist Award (C.C.C.), the Burroughs Wellcome Fund Career Awards for Medical Sciences (C.C.C.) and an National Cancer Institute K12 award (C.C.C.). A.R.M was supported by a grant from Ohio Cancer Research Associates .


  • DNA damage response
  • Fanconi Anemia
  • MutS homologs
  • Sensor


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