To cope with the threat of genome instability, cells have evolved an intricate network of mechanisms ranging from cell cycle checkpoints to specialized DNA repair pathways known as the DNA damage res…

Research group headed by Matthias Altmeyer, University of Zurich, Switzerland.

Replication stress drives genomic instability, tumour evolution and therapeutic adaptation, yet also creates exploitable vulnerabilities. In this Review, Chen and Zou discuss how chronic replication stress shapes cancer biology and how emerging therapies are targeting the pathways that enable tumour cells to survive it.

Sommerova et al. show that ataxia telangiectasia-mutated (ATM) protects replicating cells by restraining pathological bypass of endogenous oxidative base lesions through PRIMPOL-mediated repriming. When ATM is lost, post-replicative adducted ssDNA gaps accumulate, creating dependence on homologous recombination for repair and driving PARP hyperactivation and PARP inhibitor sensitivity.

Join us at the Keystone Symposia on DNA Replication: Pathway Crosstalk Shaping Physiology and Disease, April 2027, in London, with field leaders!

To cope with the threat of genome instability, cells have evolved an intricate network of mechanisms ranging from cell cycle checkpoints to specialized DNA repair pathways known as the DNA damage res…

Stability of extrachromosomal DNA (ecDNA) relies on microhomology-mediated end joining at fragile TA-rich sites, with FANCM suppressing break formation, suggesting that Polθ disruption may destab...

Whole-genome duplication (WGD), leading to polyploidy can arise in physiological and pathological contexts. WGD can occur via non-canonical cell cycles such as mitotic slippage, cytokinesis failure or...

Somatic mutations in DNMT3A and TET2 are common in age-related clonal haematopoiesis and hematopoietic neoplasms. Here, the authors show that loss of TET2, unlike DNMT3A, makes cells more sensitive to...

BRCA1-linked cancers contain abundant ~10 kb ‘Group 1’ tandem duplications (TDs). Group 1 TDs form at a Tus/Ter replication-fork barrier in DNA-end resection-defective mouse embryonic stem (mES) cells...

Cohesin-mediated loop extrusion limits sister-fork coupling and tethers nearby replication forks under replication stress, promoting fork reversal and slowing fork progression to safeguard genome...

Arabinosyl (ara) nucleoside analogues such as vidarabine (araA) and cytarabine (araC) are antimetabolites known to inhibit DNA polymerases in isolation. However, their effects on DNA synthesis catalys...

DNA modifications are central to carcinogenesis, chemotherapy drug action, neurodegeneration, and aging. Here, we present a protocol for click-code-seq, a next-generation sequencing technique for geno...

Cameron et al. show that dormant pre-replication complexes are removed upon collision with replication forks in Xenopus egg extracts. They identify FANCJ and RTEL1 as key factors in this process and s...

A biweekly scientific journal publishing high-quality research in molecular biology and genetics, cancer biology, biochemistry, and related fields

Wang et al. uncover a non-canonical role for FANCA in safeguarding genome stability during DNA replication. FANCA recruits the flap endonuclease FEN1 to lagging strands to suppress transcription-replication conflicts, a function that becomes essential under oncogene-induced replication stress, rendering tumors vulnerable to PARP inhibition despite intact homologous recombination repair.

Alternative lengthening of telomeres (ALT) counteracts telomere shortening independently of the activity of the enzyme telomerase. ALT uses telomere sequences for recombination-based telomere extension, and recent work has started to reveal how this pathway works across the cell cycle and even across cell divisions.

To cope with the threat of genome instability, cells have evolved an intricate network of mechanisms ranging from cell cycle checkpoints to specialized DNA repair pathways known as the DNA damage res…

A biweekly scientific journal publishing high-quality research in molecular biology and genetics, cancer biology, biochemistry, and related fields

Screening of chromosome arm-level aneuploidies uncovers that these alterations select for specific basal-like breast cancer driver genes, including PLGRKT, an oncogene whose tumour-promoting activity ...

Explore the causes and impact of aneuploidy in cancer, aging, and development at this global research conference.

The DNA damage response (DDR) is a complex network of cellular pathways that ensures the faithful maintenance of our genomes upon a wide array of genomic insults. To elucidate the functional architect...

Alternative lengthening of telomeres (ALT) is a recombination-mediated telomere maintenance mechanism. Although the core ALT machinery is defined, the initiating events remain unresolved. Taylor et al. demonstrate that telomeric heterochromatin enrichment drives nuclear compartmentalization, promyelocytic leukemia body nucleation, and telomere clustering, establishing a chromatin-defined environment that is permissive for recombination.

Shu et al. identify PCBP1 as an endogenous regulator that restrains PARP1, a key DNA damage sensor, under normal conditions and is released upon DNA damage through SIRT7-mediated deacetylation. Disrupting this pathway impairs DNA repair and increases DNA damage sensitivity, suggesting a potential therapeutic strategy.

AbstractMotivation. Large scale loss-of-function screens utilising CRISPR or siRNA can provide profound insights into the importance of individual genes fo

The metabolite αKG promotes carnitine synthesis and increases site-specific histone acetylation, thereby promoting homologous recombination-mediated DNA repair, which has potential implications f...

Co-directional (CD) transcription–replication conflicts (TRCs) arise when the DNA replication and transcription machineries progress along the same DNA template. Although generally considered less severe than head-on (HO) TRCs, CD TRCs are now recognized as frequent and actively regulated events that influence genome stability. The Cullin 3–Potassium channel tetramerization domain containing 10 (KCTD10) ubiquitin ligase complex functions as a bivalent sensor that detects CD collisions and directs the nonproteolytic ubiquitination of the elongation factor TCEA2, transiently remodeling RNA polymerase II to permit replisome bypass. This sensing-driven remodeling reframes CD TRCs as dynamic decision nodes where replication and transcription priorities are continuously negotiated, highlighting how conflict geometry, ubiquitin signaling, and genome maintenance are functionally integrated.

Telomere crisis contributes to cancer genome evolution. Beyond the loss of end protection, replication defects at short telomeres give rise to aberrant fork intermediates that can be resolved by microhomology-mediated end joining. Such mutagenic repair yields chromosomal fusions and complex rearrangements that shape cancer genomes.

The past two decades of PARP inhibitor synthetic lethality in cancer is explored.

Apurinic/apyrimidinic (AP) sites, also known as abasic sites, are among the most frequent DNA lesions, arising spontaneously or as intermediates in base excision repair. Their structural impediment to...