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The RAD51 recombinase plays a central role in homologous recombination (HR), which is critical for repair of DNA double-strand breaks, maintenance of genomic stability, and prevention of developmental disorders and cancer. Here, we report the identification of an RAD51-binding protein fidgetin-like 1 (FIGNL1). FIGNL1 specifically interacts with RAD51 through its conserved RAD51 binding domain. Cells depleted of FIGNL1 show defective HR repair. Interestingly, FIGNL1 is recruited to sites of DNA damage in a manner that is independent of breast cancer 2, early onset RAD51, and probably, RAD51 paralogs. Conversely, FIGNL1 depletion does not affect the loading of RAD51 onto ssDNA. Our additional analysis uncovered KIAA0146, also known as scaffolding protein involved in DNA repair (SPIDR), as a binding partner of FIGNL1 and established that KIAA0146/SPIDR acts with FIGNL1 in HR repair. Collectively, our study uncovers a protein complex, which consists of FIGNL1 and KIAA0146/SPIDR, in DNA repair and provides potential directions for cancer diagnosis and therapy.

Epithelial–mesenchymal transition (EMT) is associated with characteristics of breast cancer stem cells, including chemoresistance and radioresistance. However, it is unclear whether EMT itself or specific EMT regulators play causal roles in these properties. Here we identify an EMT-inducing transcription factor, zinc finger E-box binding homeobox 1 (ZEB1), as a regulator of radiosensitivity and DNA damage response. Radioresistant subpopulations of breast cancer cells derived from ionizing radiation exhibit hyperactivation of the kinase ATM and upregulation of ZEB1, and the latter promotes tumour cell radioresistance in vitro and in vivo . Mechanistically, ATM phosphorylates and stabilizes ZEB1 in response to DNA damage, ZEB1 in turn directly interacts with USP7 and enhances its ability to deubiquitylate and stabilize CHK1, thereby promoting homologous recombination-dependent DNA repair and resistance to radiation. These findings identify ZEB1 as an ATM substrate linking ATM to CHK1 and the mechanism underlying the association between EMT and radioresistance. Ma and colleagues show that when the EMT-associated transcription factor ZEB1 is stabilized by the ATM kinase, it interacts with the ubiquitin protease USP7 to counteract CHK1 degradation and promote DNA repair in breast cancer cells.

Fanconi anemia (FA) is caused by mutations in 13 Fanc genes and renders cells hypersensitive to DNA interstrand cross-linking (ICL) agents. A central event in the FA pathway is mono-ubiquitylation of the FANCI-FANCD2 (ID) protein complex. Here, we characterize a previously unrecognized nuclease, Fanconi anemia-associated nuclease 1 (FAN1), that promotes ICL repair in a manner strictly dependent on its ability to accumulate at or near sites of DNA damage and that relies on mono-ubiquitylation of the ID complex. Thus, the mono-ubiquitylated ID complex recruits the downstream repair protein FAN1 and facilitates the repair of DNA interstrand cross-links.

Relatlimab is a type of human immunoglobulin G4 monoclonal blocking antibody. It is the world’s first Lymphocyte-Activation Gene-3 (LAG-3) inhibitor and the third immune checkpoint inhibitor with clinical application, following PD-1 and CTLA-4. Relatlimab can bind to the LAG-3 receptor which blocks the interaction between LAG-3 and its ligand to reduce LAG-3 pathway-mediated immunosuppression and promote T-cell proliferation, inducing tumor cell death. On 18 March 2022, the U.S. FDA approved the fixed-dose combination of relatlimab developed by Bristol Myers Squibb with nivolumab, under the brand name Opdualag for the treatment of unresectable or metastatic melanoma in adult and pediatric patients aged 12 and older. This study comprehensively describes the mechanism of action and clinical trials of relatlimab and a brief overview of immune checkpoint drugs currently used for the treatment of melanoma.

Loss of REV7 is shown to regulate end resection of double-stranded DNA breaks in BRCA1-deficient cells, leading to PARP inhibitor resistance and restoration of homologous recombination; REV7 dictates pathway choice in BRCA1-deficient cells and during immunoglobulin class switching. MAD2L2/REV7 promotes genome integrity DNA polymerase ζ, composed of REV3, REV7 and an associated factor, REV1, mediates a type of DNA repair involving translesion synthesis, and hence its activity is highly mutagenic. Two studies exploring the DNA damage response have converged on REV7 (also known as MAD2L2) as a factor that, by itself, can promote maintenance of genome integrity. Several protective mechanisms that prevent telomere ends being recognized as a double-strand breaks (DSBs) and triggering an inappropriate DNA damage response were known. Jacqueline Jacobs and colleagues now show that REV7/MAD2L2 suppresses homology-dependent repair at deprotected telomeres and at irradiation-induced DSBs by inhibiting resection of the 5′ end. As a consequence, the ends are shunted into the non-homologous end-joining pathway. Sven Rottenberg and colleagues came to a similar conclusion by studying the development of resistance to PARP inhibitors. They found that REV7/MAD2L2 dictates pathway choice in BRCA-deficient cells and during immunoglobulin class switching. Error-free repair of DNA double-strand breaks (DSBs) is achieved by homologous recombination (HR), and BRCA1 is an important factor for this repair pathway 1 . In the absence of BRCA1-mediated HR, the administration of PARP inhibitors induces synthetic lethality of tumour cells of patients with breast or ovarian cancers 2 , 3 . Despite the benefit of this tailored therapy, drug resistance can occur by HR restoration 4 . Genetic reversion of BRCA1-inactivating mutations can be the underlying mechanism of drug resistance, but this does not explain resistance in all cases 5 . In particular, little is known about BRCA1-independent restoration of HR. Here we show that loss of REV7 (also known as MAD2L2) in mouse and human cell lines re-establishes CTIP-dependent end resection of DSBs in BRCA1-deficient cells, leading to HR restoration and PARP inhibitor resistance, which is reversed by ATM kinase inhibition. REV7 is recruited to DSBs in a manner dependent on the H2AX–MDC1–RNF8–RNF168–53BP1 chromatin pathway, and seems to block HR and promote end joining in addition to its regulatory role in DNA damage tolerance 6 . Finally, we establish that REV7 blocks DSB resection to promote non-homologous end-joining during immunoglobulin class switch recombination. Our results reveal an unexpected crucial function of REV7 downstream of 53BP1 in coordinating pathological DSB repair pathway choices in BRCA1-deficient cells.

China has a long history of pig rearing, and it currently raises and consumes approximately half of the pigs in the world. Major improvements have been made in pig farming in China in the last four decades with the growing application of new livestock farming technologies. Among the new improvements, the use of antibiotics in pig farming is a common but not well‐documented practise. In order to understand the behaviour of the farmers regarding antibiotic use in pig farming, we conducted a household survey in four townships of L County in Yunnan Province, China, during August 2014 and April 2015. In this survey, 404 farmer households were interviewed using a questionnaire. Among the farmers interviewed, 89% reported easy access to antibiotics, 83.7% reported experience of self‐purchasing antibiotics, and 40.3% reported that they often used antibiotics in pig farming mainly for the prevention and treatment of pig diseases. These farmers identified 20 antibiotics that they had used in pig farming 6 months before the survey. Of these, 11 and 8 antibiotics have been categorised under ‘critically important’ and ‘highly important’ antimicrobial groups, respectively, by the World Health Organization (WHO), and 12 and 8 have been categorised under the ‘Watch’ and ‘Access’ groups, respectively, as per the 2019 WHO AWaRe classification of antibiotics. Factors associated with the behaviour of self‐purchasing antibiotics included types of farms, sources of antibiotics, and previous experiences of pig diseases: those who were smallholders, buying antibiotics from veterinary drugstores and village vets, and whose pigs had suffered diseases previously were more likely to self‐purchase antibiotics for their pigs. Farmers who cleaned their pigsties less frequently and those whose pigs had suffered from diseases used antibiotics more frequently as compared to their peer farmers. This survey conducted in a county in Yunnan Province of China finds out that 83.7% of the farmers reported ‘self‐purchasing’ antibiotics for their pigs and 40.3% of the farmers expressed that they ‘often’ use antibiotics in pig farming with the major purposes being prevention and treatment of pig diseases.

The MRE11–RAD50–NBS1 (MRN) complex is well known for participating in DNA damage response pathways in all phases of cell cycle. Here, we show that MRN constitutes a mitosis-specific complex, named mMRN, with a protein, MMAP. MMAP directly interacts with MRE11 and is required for optimal stability of the MRN complex during mitosis. MMAP colocalizes with MRN in mitotic spindles, and MMAP-deficient cells display abnormal spindle dynamics and chromosome segregation similar to MRN-deficient cells. Mechanistically, both MMAP and MRE11 are hyperphosphorylated by the mitotic kinase, PLK1; and the phosphorylation is required for assembly of the mMRN complex. The assembled mMRN complex enables PLK1 to interact with and activate the microtubule depolymerase, KIF2A, leading to spindle turnover and chromosome segregation. Our study identifies a mitosis-specific version of the MRN complex that acts in the PLK1–KIF2A signaling cascade to regulate spindle dynamics and chromosome distribution.

Barrett’s oesophagus—a metaplasia that can be induced by persistent acid reflux, and predisposes patients to oesophageal cancer—arises from a population of basal cells at the gastro-oesophageal junction. Cells cross the junction of throat cancer Barrett's metaplasia occurs at the gastro-oesophageal junction, sometimes as a result of persistent acid reflux, and predisposes patients to oesophageal cancer. There has been some debate over which cells generate Barrett's oesophagus. Jianwen Que and colleagues now identify a population of basal cells at the gastro-oesophageal junction that give rise to Barrett's metaplasia in mice. Data from human samples suggest the same population of cells gives rise to Barrett's metaplasia in humans. In several organ systems, the transitional zone between different types of epithelium is a hotspot for pre-neoplastic metaplasia and malignancy 1 , 2 , 3 , but the cells of origin for these metaplastic epithelia and subsequent malignancies remain unknown 1 , 2 , 3 . In the case of Barrett’s oesophagus, intestinal metaplasia occurs at the gastro-oesophageal junction, where stratified squamous epithelium transitions into simple columnar cells 4 . On the basis of a number of experimental models, several alternative cell types have been proposed as the source of this metaplasia but in all cases the evidence is inconclusive: no model completely mimics Barrett’s oesophagus in terms of the presence of intestinal goblet cells 5 , 6 , 7 , 8 . Here we describe a transitional columnar epithelium with distinct basal progenitor cells (p63 + KRT5 + KRT7 + ) at the squamous–columnar junction of the upper gastrointestinal tract in a mouse model. We use multiple models and lineage tracing strategies to show that this squamous–columnar junction basal cell population serves as a source of progenitors for the transitional epithelium. On ectopic expression of CDX2, these transitional basal progenitors differentiate into intestinal-like epithelium (including goblet cells) and thereby reproduce Barrett’s metaplasia. A similar transitional columnar epithelium is present at the transitional zones of other mouse tissues (including the anorectal junction) as well as in the gastro-oesophageal junction in the human gut. Acid reflux-induced oesophagitis and the multilayered epithelium (believed to be a precursor of Barrett’s oesophagus) are both characterized by the expansion of the transitional basal progenitor cells. Our findings reveal a previously unidentified transitional zone in the epithelium of the upper gastrointestinal tract and provide evidence that the p63 + KRT5 + KRT7 + basal cells in this zone are the cells of origin for multi-layered epithelium and Barrett’s oesophagus.

Unrestrained 53BP1 activity at DNA double-strand breaks (DSBs) hampers DNA end resection and upsets DSB repair pathway choice. RNF169 acts as a molecular rheostat to limit 53BP1 deposition at DSBs, but how this fine balance translates to DSB repair control remains undefined. In striking contrast to 53BP1, ChIP analyses of AsiSI-induced DSBs unveiled that RNF169 exhibits robust accumulation at DNA end-proximal regions and preferentially targets resected, RPA-bound DSBs. Accordingly, we found that RNF169 promotes CtIP-dependent DSB resection and favors homology-mediated DSB repair, and further showed that RNF169 dose-dependently stimulates single-strand annealing repair, in part, by alleviating the 53BP1-imposed barrier to DSB end resection. Our results highlight the interplay of RNF169 with 53BP1 in fine-tuning choice of DSB repair pathways.

Mutations in HepA‐related protein (HARP, or SMARCAL1) cause Schimke immunoosseous dysplasia (SIOD). HARP has ATP‐dependent annealing helicase activity, which helps to stabilize stalled replication forks and facilitate DNA repair during replication. Here, we show that the conserved tandem HARP (2HP) domain dictates this annealing helicase activity. Furthermore, chimeric proteins generated by fusing the 2HP domain of HARP with the SNF2 domain of BRG1 or HELLS show annealing helicase activity in vitro and, when targeted to replication forks, mimic the functions of HARP in vivo . We propose that the HARP domain endows HARP with this ATP‐driven annealing helicase activity. HARP/SMARCAL1 has a unique annealing helicase activity that is important for the enzyme's function in stabilizing stalled replications forks and facilitating DNA repair. The authors demonstrate here that the conserved tandem HARP domain, and not the SNF2 domain, dictates the annealing helicase activity.