William Holloman



Recombinational Repair of DNA

Repair of DNA by recombination is a high fidelity molecular system whose purpose is to restore genetic material lost as a result of breakage or other severe forms of damage to DNA molecules. The process relies on utilization of a homologous DNA sequence as a template to direct repair of the damaged molecule. The paradigm for recombinational repair holds that the broken molecule is resected from the end to reveal a protruding single strand which then pairs with the homologous sequence in the undamaged molecule forming a joint molecule with a displaced strand or D-loop. After some additional processing that includes a limited amount of DNA synthesis at the D-loop and that may include resolving a Holliday junction, the broken DNA is spliced back together with lost information restored.My laboratory uses a non-mainstream yeast, Ustilago maydis, for experimental work to study individual steps in the recombinational repair process. A key component in the pathway is a homolog of BRCA2, the product of one of the major breast cancer predisposition genes in human. It, in turn, is dependent on a small polypeptide, Dss1, that serves as an essential cofactor. We are trying to understand the function of the BRCA2 homolog in the recombination process and to understand the molecular mechanism of its regulation by Dss1. Our hope is that lessons learned from these basic investigations will bear on understanding how the more complex human BRCA2 protein operates as a tumor suppressor to maintain genomic stability.

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