Targeting DNA damage sensors for cancer therapy
Year: 2025
Type: review
Abstract: DNA damage occurs from both endogenous and exogenous sources and DNA damaging agents are a mainstay in cancer therapeutics. DNA damage sensors (DDS) are proteins that recognize and bind to unique DNA structures that arise from direct DNA damage or replication stress and are the first step in the DNA damage response (DDR). DNA damage sensors are responsible for recruiting transducer proteins that signal downstream DNA repair pathways. As the initiating proteins, DDS are excellent candidates for anti-cancer drug targeting to limit DDR activation. Here, we review four major DDS: PARP1, RPA, Ku, and the MRN complex. We briefly describe the cellular DDS functions before analyzing the structural mechanisms of DNA damage sensing. Lastly, we examine the current state of the field towards inhibiting each DDS for anti-cancer therapeutics and broadly discuss the therapeutic potential for DDS targeting. • The DNA damage response is a highly coordinated network of events that is initiated by DNA damage sensors that recognize and bind to specific DNA lesions. • While the DNA damage response has been a target for cancer therapeutics, recent efforts have primarily focused on downstream events by targeting transducer kinases as opposed to the initial event performed by the DNA damage sensors. • We highlight the sensing domains of PARP1, RPA, Ku, and the MRN complex that selectively bind to unique damaged DNA structures to initiate the DNA damage response as targetable sites of inhibition. • Targeting DNA damage sensors for cancer therapeutics provides alternative advantages of enhanced selectivity and minimized off- and on-target toxicities.
Source: DNA repair
Language: English
Topic: DNA Repair Mechanisms
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: hybrid
Estimated APC paid: $3,390
OpenAlex ID: W4410048421