Microhomology-mediated end joining (MMEJ) is an evolutionary conserved pathway to repair DNA doublestrand breaks (DSBs) by annealing small stretches (2-20 bps) of overlapping sequence (microhomology; MH)flanking the break site. By design, MMEJ is highly mutagenic because it always results in the deletion of oneof the MH and the inter-MH sequences. MMEJ also frequently leads to chromosomal rearrangements due toits ability to engage in promiscuous end joining.

Replication fork stalling and collapse is a major source of genomic instability and subsequent neoplasia. Such stressed forks can be conservatively repaired and restarted using homologous recombination (HR) repair, initiated by generating an endogenous nick at the fork junction. While there are candidate nucleases for generating this DSB, most mammalian stressed forks can be restarted without these nucleases, and the origin of this nick remains undefined.

This proposal combines a team with expertise in aging, tumor immunology, tumor immunotherapy, specificgenetically modified animal models and early phase clinical trials with a computational team having greatexpertise in analyzing and modeling aging of the immune system.

Proteasome inhibitor (PI) therapy has been crucial to the improved survival of patients withmultiple myeloma (MM). Unfortunately, primary and acquired resistance to PIs contributes todisease progression and death. Obesity and/or insulin resistance are risk factors for MM mortality.Dysregulated inflammatory and metabolic factors in the metabolic syndrome or its associatedcomponents (obesity/insulin resistance/dyslipidemia) decrease the efficacy of chemotherapeuticsfor various tumor types, and likely contribute to chemoresistance and disease progression in MMpatients.