Time to Bloom

Signal transduction during DNA damage response is mediated by two proximal sensory kinases, ATM (ataxia telangiectasia-mutated) and ATR (ATM-Rad3-related) [1,2]. ATM and ATR initiate the signaling cascade via phosphorylation of its downstream checkpoint effector kinases, Chk1 and Chk2 [3]. ATR and Chk1 predominantly sense the damage in response to the stalling and subsequent collapse of the replication forks (called stalled replication forks), leading to replication arrest. On other hand ATM and Chk2 are involved in response to double strand breaks (DSBs), typically generated in vivo by exposure of cells to ionizing radiation (IR) or drugs like neocarzinostatin or bleomycin. Both stalled replication forks and DSBs lead to the generation of nuclear chromatinized foci called stalled replication foci and ionizing radiation-induced foci (IRIF), respectively. Replication arrest can also lead to the generation of DSBs [4], thereby hinting at partial common mechanistic framework in response to two common forms of DNA damage. ATM/ATR along with Chk1/Chk2, which accumulate at the chromatinized structures, are known to phosphorylate extensive network of downstream substrates in response to DNA damage [5].The protein that was initially demonstrated to accumulate at the site of IRIF was the phosphorylated form of histone variant H2AX (γH2AX) [6] (Figure 1B). However subsequently it was observed that H2AX phosphorylation was dispensable for the initial recognition of DNA breaks and was instead proposed to concentrate proteins in the vicinity of DNA lesions [7]. Since then a growing number of proteins, containing either or both the phospho-protein binding motifs BRCA1 C-terminal (BRCT) and forkhead associated (FHA) domains, have been identified to be present both at IRIF and sites of stalled replication.One such FHA-BRCT domain containing protein that accumulates at the sites of DNA damage is the mediator of DNA damage checkpoint 1 (MDC1) (Figure 1B). Recruitment of MDC1 occurs i