@article{MTMT:34169536, title = {The loss of DNA polymerase epsilon accessory subunits POLE3-POLE4 leads to BRCA1-independent PARP inhibitor sensitivity}, url = {https://m2.mtmt.hu/api/publication/34169536}, author = {Mamar, Hasan and Fajka-Boja, Roberta and Mórocz, Mónika and Pinto, Eva and Zentout, Siham and Mihut, Alexandra and Kopasz, Anna Georgina and Mérey, Mihály and Smith, Rebecca and Haracska, Lajos and Huet, Sébastien and Timinszky, Gyula}, doi = {10.1093/nar/gkae439}, journal-iso = {NUCLEIC ACIDS RES}, journal = {NUCLEIC ACIDS RESEARCH}, volume = {52}, unique-id = {34169536}, issn = {0305-1048}, abstract = {The clinical success of PARP1/2 inhibitors (PARPi) prompts the expansion of their applicability beyond homologous recombination deficiency. Here, we demonstrate that the loss of the accessory subunits of DNA polymerase epsilon, POLE3 and POLE4, sensitizes cells to PARPi. We show that the sensitivity of POLE4 knockouts is not due to compromised response to DNA damage or homologous recombination deficiency. Instead, POLE4 loss affects replication speed leading to the accumulation of single-stranded DNA gaps behind replication forks upon PARPi treatment, due to impaired post-replicative repair. POLE4 knockouts elicit elevated replication stress signaling involving ATR and DNA-PK. We find POLE4 to act parallel to BRCA1 in inducing sensitivity to PARPi and counteracts acquired resistance associated with restoration of homologous recombination. Altogether, our findings establish POLE4 as a promising target to improve PARPi driven therapies and hamper acquired PARPi resistance.}, year = {2024}, eissn = {1362-4962}, pages = {6994-7011}, orcid-numbers = {Fajka-Boja, Roberta/0000-0001-5331-8280} } @article{MTMT:33955642, title = {HPF1-dependent histone ADP-ribosylation triggers chromatin relaxation to promote the recruitment of repair factors at sites of DNA damage}, url = {https://m2.mtmt.hu/api/publication/33955642}, author = {Smith, Rebecca and Zentout, Siham and Rother, Magdalena and Bigot, Nicolas and Chapuis, Catherine and Mihut, Alexandra and Zobel, Florian Franz and Ahel, Ivan and van Attikum, Haico and Timinszky, Gyula and Huet, Sebastien}, doi = {10.1038/s41594-023-00977-x}, journal-iso = {NAT STRUCT MOL BIOL}, journal = {NATURE STRUCTURAL & MOLECULAR BIOLOGY}, volume = {30}, unique-id = {33955642}, issn = {1545-9993}, abstract = {Poly(ADP-ribose) polymerase 1 (PARP1) activity is regulated by its co-factor histone poly(ADP-ribosylation) factor 1 (HPF1). The complex formed by HPF1 and PARP1 catalyzes ADP-ribosylation of serine residues of proteins near DNA breaks, mainly PARP1 and histones. However, the effect of HPF1 on DNA repair regulated by PARP1 remains unclear. Here, we show that HPF1 controls prolonged histone ADP-ribosylation in the vicinity of the DNA breaks by regulating both the number and length of ADP-ribose chains. Furthermore, we demonstrate that HPF1-dependent histone ADP-ribosylation triggers the rapid unfolding of chromatin, facilitating access to DNA at sites of damage. This process promotes the assembly of both the homologous recombination and non-homologous end joining repair machineries. Altogether, our data highlight the key roles played by the PARP1/HPF1 complex in regulating ADP-ribosylation signaling as well as the conformation of damaged chromatin at early stages of the DNA damage response.Smith, Zentout et al. investigate the role of HPF1 in DNA repair using live-cell imaging methods and find that HPF1-dependent histone ADP-ribosylation drives early process in DNA repair, including chromatin relaxation and repair factor recruitment.}, year = {2023}, eissn = {1545-9985}, pages = {678-691}, orcid-numbers = {Zentout, Siham/0000-0002-9005-9588; Chapuis, Catherine/0000-0002-3765-0969} }