In the fission yeast Schizosaccharomyces pombe, a chromosomal imprinting event controls the asymmetric pattern of mating-type switching. The orientation of DNA replication at the mating-type locus is instrumental in this process. However, the factors leading to imprinting are not fully identified and the mechanism is poorly understood. Here, we show that the replication fork pause at the mat1 locus (MPS1), essential for imprint formation, depends on the lysine-specific demethylase Lsd1. We demonstrate that either Lsd1 or Lsd2 amine oxidase activity is required for these processes, working upstream of the imprinting factors Swi1 and Swi3 (homologs of mammalian Timeless and Tipin, respectively). We also show that the Lsd1/2 complex controls the replication fork terminators, within the rDNA repeats. These findings reveal a role for the Lsd1/2 demethylases in controlling polar replication fork progression, imprint formation, and subsequent asymmetric cell divisions.
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http://dx.doi.org/10.1016/j.celrep.2012.10.011 | DOI Listing |
Cell Death Dis
January 2025
Tianjian Laboratory of Advanced Biomedical Sciences, Academy of Medical Sciences, Zhengzhou University, Zhengzhou, Henan, China.
Mitochondrial oxidative phosphorylation (OXPHOS) is a therapeutic vulnerability in glycolysis-deficient cancers. Here we show that inhibiting OXPHOS similarly suppresses the proliferation and tumorigenicity of glycolytically competent colorectal cancer (CRC) cells in vitro and in patient-derived CRC xenografts. While the increased glycolytic activity rapidly replenished the ATP pool, it did not restore the reduced production of aspartate upon OXPHOS inhibition.
View Article and Find Full Text PDFNat Commun
January 2025
DNA Replication Group, Institute of Clinical Sciences, Faculty of Medicine, Imperial College London, London, UK.
Human DNA licensing initiates replication fork assembly and DNA replication. This reaction promotes the loading of the hMCM2-7 complex on DNA, which represents the core of the replicative helicase that unwinds DNA during S-phase. Here, we report the reconstitution of human DNA licensing using purified proteins.
View Article and Find Full Text PDFProc Natl Acad Sci U S A
January 2025
Département de Biologie, Université de Sherbrooke, Sherbrooke, QC J1K 2R1, Canada.
To achieve replicative immortality, cancer cells must activate telomere maintenance mechanisms. In 10 to 15% of cancers, this is enabled by recombination-based alternative lengthening of telomeres pathways (ALT). ALT cells display several hallmarks including heterogeneous telomere length, extrachromosomal telomeric repeats, and ALT-associated PML bodies.
View Article and Find Full Text PDFDNA Repair (Amst)
December 2024
Department of Data Science, Dana-Farber Cancer Institute, Boston, MA 02115, USA; Department of Pathology, Harvard Medical School, Boston, MA 02115, USA; Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, MA 02142, USA.
Tandem duplications (TD) are among the most frequent type of structural variant (SV) in the cancer genome. They are characterized by a single breakpoint junction that defines the boundaries and the size of the duplicated segment. Cancer-associated TDs often increase oncogene copy number or disrupt tumor suppressor gene function, and thus have important roles in tumor evolution.
View Article and Find Full Text PDFGenome Biol
December 2024
Division of Tumor Biology & Immunology, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX, Amsterdam, The Netherlands.
Background: DNA damage tolerance (DDT) enables replication to continue in the presence of fork stalling lesions. In mammalian cells, DDT is regulated by two independent pathways, controlled by the polymerase REV1 and ubiquitinated PCNA, respectively.
Results: To determine the molecular and genomic impact of a global DDT defect, we studied Pcna;Rev1 compound mutants in mouse cells.
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