DRUSE

Last month (December 2008)  in the Journal of Biological Chemistry, Rebecca Chanoux and colleagues reported the results of their studies on ATR and H2AX. They wrote:

“If ATR prevents the collapse of stalled replication forks into DSBs, and H2AX facilitates HR-mediated restart, the combined deficiency in ATR and H2AX would be expected to dramatically enhance the accumulation of DSBs upon replication fork stalling. Herein, we utilize both partial and complete elimination of ATR and H2AX to demonstrate that these genes work cooperatively in non-redundant pathways to suppress DSBs during S phase.”

They hypothesized that H2AX participates in a Rad51-mediated suppression of DSBs generated in  the absence of ATR.

They found that increased Rad51 focal accumulation in ATR-deficient cells is dependent on H2AX, and deficiencies in  both ATR and H2AX lead to synergistic increases in chromatid breaks and translocations.

They discussed further that the ATM and DNA-PK phosphorylation site on H2AX (Ser139) is required for genome stabilization in ATR’s absence; therefore, phosphorylation of H2AX by ATM and DNA-PKcs plays a pivotal role in suppressing DSBs during DNA synthesis in instances of ATR pathway failure.

Their results imply that fork stabilization (ATR-dependent) and H2AX/ATM/DNA-PKcs-dependent pathways cooperate to suppress DSBs when replication stalls.