( ects in double-strand break repair by d...)DNA repair proteins monitored at double-strand break

ects in double-strand break repair by disrupting the signaling processes triggered by the break. "A lack of functioning ATM causes ataxia-teleangiectasia, a disease that causes a variety of debilitating problems, such as neurodegeneration, cancer and sensitivity to irradiation leading to double-strand breaks that are not repaired," Kastan said. "And a lack of NBS1 causes Nijmegen breakage syndrome, another disease that leaves its victims at high risk for cancer and higher sensitivity to DNA-damaging radiation. So this work has important medical implications for these and other diseases linked to disruption of double-strand break repair."

The assay, developed by Elijahu Berkovich, Ph.D., in Kastan’s laboratory, demonstrates how key repair proteins, such as ATM, NBS1, XRCC4 and gamma-H2AX, interact to coordinate repair of double-strand breaks. For example, the investigators showed that NBS1 recruits ATM to the break; and that ATM and NBS1 cooperate to disrupt nucleosomes—the compact packages formed when strands of DNA wind around proteins, called histones, like thread around a spool. Disruption of the nucleosome at the site of a double-strand break allows the DNA to unravel and expose the area to repair proteins; the loss of functioning ATM and NBS1 blocks this important process. The team also showed that both NBS1 and ATM are needed to ensure that the repair factor, XRCC4, arrives at the double-strand break to help repair the damage.

In addition, the investigators showed that ATM initially binds to DNA both at the site of the break as well as on each side of it. However, XRCC4 later takes the place of ATM molecules at the break while the ATM molecules on either side of the break stay in place. The researchers suggested that ATM had been displaced or moved so that the repair proteins could gain access to the damaged DNA site.

The findings also suggested that before ATM can move to the double-strand break, it must first become activated
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Source:St. Jude Children's Research Hospital

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