DNA repair helicases: from mechanistic understanding to therapeutic implications

The maintenance of genomic integrity is paramount for normal cell physiology and survival as well as avoidance of carcinogenesis. Cellular DNA is periodically subjected to a myriad of exogenous and endogenous threats and requires constant monitoring to limit genomic instability. To this end, cells possess an intricate DNA damage response and repair (DDR) module comprised of different classes of protein players. The DNA helicases, ATP-dependent enzymes that unwind the DNA double helix, are one such important class of proteins, which act as a linchpin between the recognition and resolution of DNA damage via facilitating various DNA repair processes. Dysfunction or absence of DDR helicase function is implicated in several human disorders including Bloom syndrome, Werner syndrome, Rothmund-Thomson syndrome, and Fanconi anemia. Somatic helicase mutations or dysregulation of helicase function can also contribute to cancer development, progression, and chemotherapy sensitivity, making helicases a promising target class for chemotherapeutic drug intervention. In addition, recent discoveries have identified some DDR helicases in novel synthetic lethal interactions. In this critical review, we will focus on human DNA helicases that are directly or indirectly involved in DDR with special emphasis on their mechanistic actions and clinical implications.