Chromatin Remodeling Complex are Linked to DNA Damage Checkpoint Responses

Xuetong Shen, Ph.D.
University of Texas M.D. Anderson Cancer Center
P30ES007784

NIEHS-supported scientists at the University of Texas M.D. Anderson Cancer Center have found that a signaling pathway and a chromatin remodeling pathway interact in response to DNA damage. The team suggests that this finding could open an entirely new category of targets for attacking cancer.

In response to DNA damage, checkpoint genes temporarily halt cellular division while DNA repair genes mobilize. The ATM/ATR kinases are known to regulate DNA repair and checkpoint pathways by phosphorylating other proteins involved in DNA damage control. The group found that one of these phosphorylated proteins is a subunit of the chromatin remodeling complex called INO80. Additional experiments showed that the activated protein regulates checkpoint pathways but not DNA repair pathways.

Chromatin remodeling results in greater access to DNA so that repair machinery can attach and fix the damaged DNA strands. The team discovered that the les4 subunit of the INO80 remodeling complex is activated by the ATM/ATR kinases, a necessary step for certain cellular checkpoints to work properly. Mutation of les4’s phosphorylation sites did not significantly affect DNA repair processes, but did influence DNA damage checkpoint responses. These findings establish the chromatin remodeling complex and a component in the DNA damage signaling patheway that controls checkpoint responses.

Citation: Morrison AJ, Kim JA, Person MD, Highland J, Xiao J, Wehr TS, Hensley S, Bao Y,Shen J, Collins SR, Weissman JS, Delrow J, Krogan NJ, Haber JE, Shen X. Mec1/Tel1 phosphorylation of the INO80 chromatin remodeling complex influences DNA damage checkpoint responses. Cell. 2007 Aug 10;130(3):499-511.