HUWE1 is a multi‐faceted E3 ubiquitin ligase of the HECT family with many confirmed substrates, but mechanistic understanding of its functional roles in signaling pathways remains limited. In this issue of EMBO Reports, Choe et al demonstrate a novel function for HUWE1 in promoting DNA damage tolerance mechanisms to bypass DNA lesions during replication stress, thereby preserving genome stability. The authors connect this role for HUWE1 with its function in maintaining H2AX monoubiquitination levels for efficient signaling at stalled replication forks . Thus, this work highlights HUWE1 as a novel player in the replication stress response and prompts further investigation of its regulation during replication and other cellular processes.
See also: KN Choe et al (June 2016)
The process of DNA replication is inherently challenging, and even when conditions are ideal, obstacles to replication fork progression contribute to “replication stress”. Replication fork stalling and collapse resulting from such perturbations potentially compromise efficient replication completion, increasing genome instability and tumorigenesis. Fortunately, cells have multiple ways to cope with replication stress, including DNA damage tolerance mechanisms that promote the restart of stalled forks through bypass of DNA lesions. Despite much attention to the topic in recent years, mechanisms promoting fork restart during the replication stress response remain poorly understood in mammalian cells.
Recent findings from Choe et al  identify HUWE1 (also named ARF‐BP1, HECTH9, MULE, and Lasu1) as a novel regulator of replication fork restart following replication stress. HUWE1 has been previously shown to target a broad range of substrates for degradation, but its function in signaling pathway regulation has remained controversial …