Promoted Repair of DNA Double-Strand Break by MRNIP

Via in vitro and in vivo studies, this study discloses the underlying mechanism of DNA double-strand break (DSB) repair carried out by MRE11/RAD50/NBS1 (MRN) complex interacting protein (MRNIP). In intrinsically disordered region, the MRNIP forms condensates which then concentrates MRN complex into liquid-like droplets. When DSBs are formed and sensed, the MRNIP condensates proceed swiftly to the damaged DNA and promote the binding of damaged DNA to the concentrated MRN complex. This results in the autophosphorylation of ataxia telangiectasia mutated (ATM) followed by an accelerated DNA damage response and DSB end resection, promoting the homologous recombination (HR)-mediated DSB repair. Meanwhile, compared to normal rectum tissues, lower MRNIP expression is observed in radiation proctitis tissues. This implies that targeting MRNIP condensates could help to sensitize tumor cells to radiotherapy and lead to the development of radiation proctitis. In order to complement the existing findings, the authors are looking forward to the direct uncovering of the pathway underlying the impact of MRNIP condensates on MRN-mediated DSB sensing.

The repair of DNA double-strand breaks (DSBs) is no doubt a critical process to maintain the sustainability of organisms. Defective DSBs repair is very likely to cause devastating consequences such as cancer, embryonic death, and neurological disorders. In DSBs repair, the MRE11/RAD50/NBS1 (MRN) complex acts as a sensor towards DSBs and also an initiator of DNA damage responses. However, when DSBs is formed, it is still elusive with regards to how the MRN complex senses and binds to DNA rapidly. In the mean time, liquid-liquid phase separation (LLPS) is a process whereby molecules condense into a dense phase (high concentrated liquid droplets) whilst the remaining solution forms a dilute phase. Various studies associated LLPS to the repair of DNA damage and this indicated that LLPS might play a crucial role in DSBs repair. Therefore, an international collaboration with Sun Yat-sen University Cancer Center (China) and Sun Yat-sen University (China) took place to conduct an in-depth investigation on the role of MRNIP condensate in regulating HR-mediated DSB repair as well as the impact of LLPS on the function of MRNIP. The output of this study is an essential reference for future research which target to overcome diseases related to defective DSBs repairs.

DNA DSBs, the most severe type of DNA damage, leads to apoptosis, gene mutation, and carcinogenesis if left unattended. As an effort to overcome defective DNA DSBs repair, a strong fundamental understanding about the relevant underlying mechanisms must be acquired. The pathway unveiled in this study provides significant insights on the pathway of DSBs repair and, thus, this study is very well-aligned with UNSDG 3: Good Health & Well-Being.