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Chromatin remodeling complex connected to DNA damage control

HOUSTON - When molecular disaster strikes, causing structural damage to DNA, players in two important pathways talk to each other to help contain the wreckage, scientists at The University of Texas M. D. Anderson Cancer Center report in the August edition of Cell.

This connection between a signaling pathway crucial to DNA damage control and a pathway known as chromatin remodeling "opens an entirely new category of targets for potentially attacking cancer," says senior author Xuetong "Snow" Shen, Ph.D., an assistant professor in M. D. Anderson's Department of Carcinogenesis at the Science Park - Research Division in Smithville, Texas.

If DNA damage is like a fire that spreads when impaired cells divide and multiply, then the DNA checkpoint and repair system can be considered a first-response firebreak. Checkpoint genes temporarily halt a cell's division and assess its DNA. The "fire" is either doused by DNA repair or by programmed destruction of the cell.

The ATM/ATR kinases are known to regulate DNA repair and checkpoint pathways, Shen explains, by attaching phosphate groups to other proteins involved in damage control. When ATM and ATR are themselves damaged, they cause genome instability and fuel cancer growth.

"We found that one of the proteins phosphorylated was a unit of a chromatin remodeling complex we call INO80," Shen says. "We subsequently found that phosphoryllation of this subunit regulates checkpoint pathways, but not DNA repair pathways."

A cell's DNA resides in chromosomes found in the cell nucleus, but it's a bit more complex than just DNA itself, Shen explains. DNA is tightly intertwined with proteins known as histones and assembled in histone/DNA units called nucleosomes along the connecting length of a string of DNA.

"This structure is often referred to as beads on a string," Shen says, and is collectively known as chromatin.

"Chromatin creates barriers to DNA against anythi
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Contact: Scott Merville
sdmervil@mdanderson.org
713-792-0661
University of Texas M. D. Anderson Cancer Center
9-Aug-2007


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