Scientists at Scripps Research have revealed how cells activate an emergency DNA repair system when standard pathways fail, a process that some cancer cells rely on for survival. This backup mechanism, known as break-induced replication, is error-prone and could become a target for new cancer therapies. The findings highlight vulnerabilities in tumors with defective SETX protein.
DNA in cells faces constant threats, including double-strand breaks that sever both strands of the helix. Normally, cells use precise repair systems to mend such damage. However, when these fail—often due to genetic tangles like R-loops, which are RNA-DNA structures—cells switch to a less reliable option called break-induced replication (BIR).
R-loops, while useful for cell functions, must be controlled to avoid genome instability. "R-loops are important for many different cell functions, but they must be tightly controlled," says Xiaohua Wu, a professor at Scripps Research and senior author of the study published in Cell Reports. Without proper regulation, they accumulate and heighten vulnerability.
The research centered on senataxin (SETX), a helicase protein that unwinds tangled genetic material. Mutations in the SETX gene link to neurological conditions like ataxia and amyotrophic lateral sclerosis (ALS), as well as uterine, skin, and breast cancers. In cells lacking functional SETX, R-loops build up at double-strand break sites, disrupting usual repair signals.
This leads to excessive trimming of broken DNA ends, exposing single-stranded sections that trigger BIR. BIR rapidly copies long DNA stretches to reconnect breaks but introduces errors, akin to a hasty emergency fix. "We were surprised but excited to find that the cell turns on an emergency DNA repair mechanism called break-induced replication (BIR)," Wu notes. "It's like an emergency repair team that works intensively but makes more mistakes."
SETX-deficient cells depend on BIR for survival, involving proteins like PIF1, RAD52, and XPF. Blocking these creates synthetic lethality, killing cancer cells while sparing healthy ones. "What's important is that these aren't essential in normal cells, which means we could selectively kill SETX-deficient tumors," Wu explains.
Though SETX mutations are rare, many cancers accumulate R-loops through other means, such as oncogene activation or estrogen signaling in breast cancers. The team, including Tong Wu, Youhang Li, Yuqin Zhao, Sameer Bikram Shah, and Linda Z. Shi, is now seeking inhibitors for BIR factors with low toxicity. The work received support from National Institutes of Health grants.
