Interplay between Fanconi Anemia Pathway and DNA Damage Response induced by DNA Interstrand Crosslinks

Thursday, November 07, 2013 — Poster Session II
12:00 p.m. – 2:00 p.m.	FAES Academic Center (Upper-Level Terrace)	NIA	CHEMCELL-21

Authors

M Paramasivam
MM Seidman

Abstract

Among the most challenging DNA lesions are the interstrand crosslinks (ICLs). They are potent blocks to replication and transcription, contributes to genomic instability and aging. Sensitivity to crosslinking agents is a hallmark of Fanconi Anemia (FA), features of premature aging and an increased risk of cancer development. A central event in the FA pathway is the monoubiquitination of FANCD2. FANCD2 deficient cells are hypersensitive to cross-linking agents. FancD2 localize to sites of DNA damage and stalled replication forks, believed to play important role in ICL repair. But the protein partners required for FANCD2 localization are obscure. We found that ICLs can activate a vigorous DDR throughout the cell cycle, including members of the FA pathway, such as FANCD2. We have found phosphorylated H2AX and MDC1, were required for recruitment of FANCD2 in G1 cells, but not in S phase. H2A ubiquitylation (uH2A) was also important for recruitment of FANCD2. We found the first evidence for an interaction between FANCD2 and uH2A following ICL formation. Our results also indicate that psoralen ICLs induce a DDR response, which differs from other forms of DNA damage. Furthermore, we show that the FA pathway response can be distinguished by cell cycle phase.