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PARP ENZYMES AND BRCA PROTEINS

ARE

IMPORTANT

FOR DNA REPAIR1

This repair function is thought to maintain DNA replication and cell survival. In normal cells, DNA damage can happen through single-strand breaks (SSBs) and double-strand breaks (DSBs). With BRCA1 or BRCA2 mutations, tumor cells have impaired DNA repair function. gBRCA-positive tumors are dependent on PARP and other proteins for DNA repair.1,2

In gBRCA-mutated tumor cells, the loss of BRCA function may lead to an overreliance on PARP enzymes to repair damaged DNA.1

NORMAL CELL2-6

dnk1

PARP and BRCA are important components of normal DNA damage repair, specifically the repair of SSBs and DSBs, respectively. Their repair functions are thought to enable DNA replication and normal cell survival.2-6

BRCA-MUTATED TUMOR CELL2,4-6

dnk2

Unrepaired SSBs can lead to DSBs, which BRCA-mutated tumor cells are unable to repair. In the absence of BRCA1 or BRCA2 proteins, PARP enzymes continue to repair SSBs through the recruitment of DNA repair proteins. PARP repair of SSBs enables DNA replication and tumor cell survival.2,4-6

References: 1. Gavande NS, VanderVere-Carozza PS, Hinshaw HD, et al. DNA repair targeted therapy: the past or future of cancer treatment? Pharmacol Ther. 2016;160:65-83. 2. Livraghi L, Garber JE. PARP inhibitors in the management of breast cancer: current data and future prospects. BMC Med. 2015;13:188. doi:10.1186/s12916-015-0425-1. 3. Shao G, Lilli DR, Patterson-Fortin J, Coleman KA, Morrissey DE, Greenberg RA. The Rap80-BRCC36 de-ubiquitinating enzyme complex antagonizes RNF8-Ubc13-dependent ubiquitination events and DNA double strand breaks. Proc Natl Acad Sci U S A. 2009;106(9):3166-3171. 4. Lee JM, Ledermann JA, Kohn EC. PARP inhibitors for BRCA1/2 mutation-associated and BRCA-like malignancies. Ann Oncol. 2014;25(1):32-40. 5. Lupo B, Trusolino L. Inhibition of poly(ADP-ribosyl)ation in cancer: old and new paradigms revisited. Biochim Biophys Acta. 2014;1846(1):201-215. 6. Rouleau M, Patel A, Hendzel MJ, Kaufmann SH, Poirier GG. PARP inhibition: PARP1 and beyond. Nat Rev Cancer. 2010;10(4):293-301. doi:10.1038/nrc2812.

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