RECQL5 and BLM exhibit divergent functions in cells defective for the Fanconi anemia pathway | Zendy

Tae Moon Kim | Zendy; MiYoung Son | Zendy; Sherry G. Dodds | Zendy; Lingchuan Hu | Zendy; Guangbin Luo | Zendy; Paul Hasty | Zendy

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RECQL5 and BLM exhibit divergent functions in cells defective for the Fanconi anemia pathway

Author(s) -

Tae Moon Kim,

MiYoung Son,

Sherry G. Dodds,

Lingchuan Hu,

Guangbin Luo,

Paul Hasty

Publication year - 2014

Publication title -

nucleic acids research

Language(s) - English

Resource type - Journals

SCImago Journal Rank - 9.008

H-Index - 537

eISSN - 1362-4954

pISSN - 0305-1048

DOI - 10.1093/nar/gku1334

Subject(s) - biology , rad51 , fanconi anemia , homologous recombination , postreplication repair , bloom syndrome , dna replication , dna repair , dna damage , genome instability , camptothecin , microbiology and biotechnology , minichromosome maintenance , replication factor c , chromosomal fragile site , helicase , genetics , dna , control of chromosome duplication , dna mismatch repair , gene , biochemistry , rna , chromosome

Fanconi anemia (FA) patients exhibit bone marrow failure, developmental defects and cancer. The FA pathway maintains chromosomal stability in concert with replication fork maintenance and DNA double strand break (DSB) repair pathways including RAD51-mediated homologous recombination (HR). RAD51 is a recombinase that maintains replication forks and repairs DSBs, but also rearranges chromosomes. Two RecQ helicases, RECQL5 and Bloom syndrome mutated (BLM) suppress HR through nonredundant mechanisms. Here we test the impact deletion of RECQL5 and BLM has on mouse embryonic stem (ES) cells deleted for FANCB, a member of the FA core complex. We show that RECQL5, but not BLM, conferred resistance to mitomycin C (MMC, an interstrand crosslinker) and camptothecin (CPT, a type 1 topoisomerase inhibitor) in FANCB-defective cells. RECQL5 suppressed, while BLM caused, breaks and radials in FANCB-deleted cells exposed to CPT or MMC, respectively. RECQL5 protected the nascent replication strand from MRE11-mediated degradation and restarted stressed replication forks in a manner additive to FANCB. By contrast BLM restarted, but did not protect, replication forks in a manner epistatic to FANCB. RECQL5 also lowered RAD51 levels in FANCB-deleted cells at stressed replication sites implicating a rearrangement avoidance mechanism. Thus, RECQL5 and BLM impact FANCB-defective cells differently in response to replication stress with relevance to chemotherapeutic regimes.

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