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A new protein, Tudor interacting repair regulator (TIRR), affects DNA repair by masking the chromatin interaction domain of 53BP1, thereby preventing its recruitment to double-strand breaks.

TIRR interacts directly with 53BP1, restricting its access to DNA double-strand breaks (DSBs) and its association with p53. Here, the authors show that the lncRNA NEAT1, regulated by TDP-43, destabilizes the TIRR/53BP1 complex in G1, promoting 53BP1’s function in DSB repair and p53 transactivation.

BRCA1/2 mutations are known to increase risk of breast and ovarian cancer but carrier status in healthy individuals is unknown without genetic testing. Here, the authors created a circulating miRNA signature to predict BRCA1/2 carrier status in healthy individuals to aid the decision process on genetic testing.

p53-binding protein 1 (53BP1) is a component of the DNA double-strand break signaling and repair. Here the authors show that that loss of 53BP1 in cancer cells leads to cGAS/STING pathway activation and anti-tumor immune responses in ovarian and pancreatic cancer models.

Both microRNAs (miRNAs) and other small non-coding RNAs (ncRNAs) are induced by DNA breaks and have been linked to the DNA damage response. This interplay between ncRNAs and repair factors may help to ensure efficient DNA repair and maintenance of genome stability.

Cyclin B1 is a mitotic co-factor of CDK5.

Upon formation of DNA double-strand breaks, many protein phosphorylation events are involved in activating cellular responses and DNA repair processes. Now a phosphatase complex containing PP4C and regulatory subunit PP4R2 is shown to dephosphorylate RPA2, and this is necessary to allow efficient DNA repair via homologous recombination.

Most terminally differentiated cells have a diminished capacity to respond to and repair DNA damage. Now a microRNA is shown to have a role in this phenotype in blood cells: miR-24 is upregulated in blood cells differentiated in vitro and decreases the levels of H2AX, a histone variant with a key role in the response to DNA double-stranded breaks.

Here, the authors show that DYNLL1 accumulates at DNA double-strand breaks via 53BP1, where it inhibits MRE11-dependent end resection by disrupting its dimerization, and it restricts recruitment of the Shieldin complex.

DYNLL1 antagonizes end resection of DNA double-strand breaks, thereby inhibiting homologous repair, and the loss of DYNLL1 correlates with poor progression-free survival of patients with BRCA1-mutant ovarian cancer.

Regulation of post translational modification of 53BP1 is critical for genome integrity and regulation of DNA damage response. Here the authors reveal a CDK5-PP4 phospho-signaling cascade that leads 53BP1 to sites of DNA damage.

Structural and functional dissection of the TIRR–53BP1 complex shows that TIRR acts as a regulatory switch that blocks 53BP1 binding to chromatin to direct DNA repair, and it releases 53BP1 in response to DNA damage by binding RNA.

In cancer, the impact on cellular fitness of copy-number gains affecting collaterally-amplified genes remains poorly understood compared to oncogenes. Here, the authors integrate genomic data from tumours and cell lines and identify a class of ‘Amplification-Related Gain Of Sensitivity’ (ARGOS) genes, with potential therapeutic applications.

Cells rely on two main pathways to repair DNA lesions, homologous recombination and non-homologous end-joining, and how they decide to use one machinery over the other is not clear. A recent study identifies ASTE1 as a regulator controlling pathway choice.

A phospho-switch is identified in the shelterin subunit TRF2 that regulates transient recruitment of the RTEL1 helicase to, and release from, telomeres, and provides a narrow window during which RTEL1 can unwind t-loops to facilitate telomere replication.

Here, using small molecule antagonists and protein engineering, the authors identify an autoinhibited state of 53BP1 leading to its chromatin binding surface being obstructed. Such small molecule ligands present a potential avenue for the development of cancer therapy drugs.

A randomized phase 2 study recently showed that the addition of ATR inhibitor berzosertib to gemcitabine improved PFS compared to gemcitabine alone in patients with ovarian cancer. In this preplanned exploratory study, the authors demonstrate that a genomic biomarker of replication-stress is associated with outcome to gemcitabine alone and may predict which patients benefit from addition of the ATR inhibitor berzosertib.

A Phase I/II trial previously revealed variable anti-tumor efficacy of the PARP inhibitor niraparib in combination with the PD-1 inhibitor pembrolizumab in platinum-resistant ovarian cancer patients. Here, the authors perform an integrated genomic and immunomics analysis of tumor samples from the same patients and find potential predictive biomarkers of response to such combination therapy.

Clairmont et al. find that the TRIP13 ATPase regulates REV7–Shieldin dissociation to promote homology-directed repair and suppress non-homologous end joining, and show the importance of PARPi resistance in BRCA1-deficient cancers.

Chromosomes within micronuclei are shown to be damaged during S phase and become highly fragmented, and the damaged pieces can be reincorporated into the genome.

Argonaute family members are effectors in small RNA-mediated silencing. In vitro analysis of the four human Argonautes demonstrates that AGO1 and AGO2 mediate multiple rounds of microRNA strand dissociation, mediate siRNA passenger-strand cleavage activity, and indicate distinct mechanisms from mRNA endonuclease activity.

Replication stress is a cause of genome instability in cancer cells. This Review discusses strategies to increase replicative stress by inhibiting the checkpoint kinases that coordinate DNA damage response and cell cycle, as well as combination strategies with other targeted therapies.