DNA2, a new player in telomere maintenance and tumor suppression

Telomeres form special structures to shield chromosome ends from inappropriate DNA repair activities, therefore protecting genome stability. Telomeres are maintained by telomerase, telomerespecific binding proteins termed shelterins, as well as proteins involved in general DNA metabolism. The primary function of telomerase is to extend short telomeres, thereby revoking the proliferation barrier caused by telomere attrition. The shelterin complex, comprising of TRF1, TRF2, POT1, TPP1, TIN2, RAP1, binds to telomere DNA and suppresses ATM/ ATR-mediated DNA damage response, thereby inhibiting DNA repair activities at telomeres. Aside from shelterin proteins, numerous proteins involved in general DNA repair/replication also associate with telomeres and play essential roles in maintaining telomere integrity. Although much has been learned about the functions of telomerase and shelterins in telomere maintenance, understanding of the roles of non-shelterin proteins has lagged. We have recently identified mammalian DNA2 as a new player in protecting telomere integrity. Complete DNA2 knockout in mice is embryonic lethal, suggesting that DNA2 is an essential gene. DNA2+/− mice are viable, but with high occurrence of lung adenocarcinoma, lymphoma, and hepatoma. Mouse embryonic fibroblast (MEF) cells derived from DNA2+/− mice display a variety of genome instabilities, including chromosome bridges and aneuploidy. Notably, telomeres in both normal and tumor tissues derived from DNA2+/− mice are significantly shorter than wild-type controls. DNA2 deficiency also induces DNA damage response at telomeres, suggesting that DNA2, a new player in telomere maintenance and tumor suppression