Abstract B07: Learning from human tumors: Modeling of Mre11 complex patient mutations in yeast

The Mre11 complex plays a central role in the eukaryotic DNA damage response (DDR) in which it acts as a sensor of DNA double strand breaks (DSBs), and thereby governs DNA damage signaling as well as DSB repair. The complex is comprised of Mre11, Rad50, and Nbs1 (or Xrs2 in budding yeast), with dimers of Rad50 and Mre11 forming its core and a Nbs1/Xrs2 protomer binding to each Mre11. The Mre11 complex globular domain harbors all enzymatic and DNA binding functions of the Mre11 complex and is a very dynamic domain regulated by conformational changes induced by Rad50 ATP binding and hydrolysis cycles. It was suggested that the ATP-bound closed form of the complex promotes Mre11 complex role in ATM/Te1l signaling, whereas ATP hydrolysis opens the globular domain, and renders the Mre11 nuclease domain accessible to the DNA substrate to promote its role in DSB repair. We have recently shown that Mre11 complex role in ATM/Te1l signaling and DSB repair are genetically separable. The curative response of a patient with metastatic small cell cancer to combined checkpoint kinase 1 (Chk1) inhibition and DNA damaging chemotherapy was promoted in part by the simultaneous inhibition of both the ATR and the ATM axes of the DDR, as the tumor harbored a missense mutation within the Rad50 ATPase D-loop domain attenuating ATM signaling. To date, targeted tumor sequencing identified more than 800 missense mutations within Mre11 complex genes spanning various types of tumors, with some mutations ...
Source: Molecular Cancer Research - Category: Cancer & Oncology Authors: Tags: DNA Damage Signaling: Poster Presentations - Proffered Abstracts Source Type: research