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Is NHEJ a tumor suppressor or an aging suppressor?

Paul Hasty

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Tumor suppressors are longevity assurance genes that ensure early life fitness. Genes are defined as tumor suppressors if their mutation predisposes the animal to cancer (a phenotype-based definition). Tumor suppressors fall into two categories: caretakers and gatekeepers. Caretakers suppress cancer by repairing damaged DNA while gatekeepers suppress cancer by halting the cell cycle long enough to repair damaged DNA. If the damage is irreparable, gatekeepers induce either apoptosis or senescence. These responses are deleterious to the cell but protect the organism. p53 is the best-known gatekeeper because it is mutated in over half of all cancers. Nonhomologous end joining (NHEJ) is considered a caretaker since it repairs DNA double-strand breaks that would otherwise lead to gross chromosomal rearrangements (GCRs). NHEJ-mutant mice display increased GCRs, but without increased cancer. Instead these mice show early aging. This commentary focuses on the role NHEJ has on aging and cancer. I propose that NHEJ evolved to reduce GCRs and moderate gatekeeper responses that would otherwise cause early aging. Furthermore, NHEJ did not evolve to suppress tumors and any observed tumor suppression is merely circumstantial to unnatural laboratory conditions coupled with human bias that favors defining all DNA repair pathways as caretakers.

Authors

Paul Hasty

University of Texas Health Science Center; San Antonio, TX

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