X Chromosome Crossover Formation and Genome Stability in Caenorhabditis elegans Are Independently Regulated by xnd-1.
The germ line efficiently combats numerous genotoxic insults to ensure the high fidelity propagation of unaltered genomic information across generations. Yet, germ cells in most metazoans also intentionally create double-strand breaks (DSBs) to promote DNA exchange between parental chromosomes, a process known as crossing over. Homologous recombination is employed in the repair of both genotoxic lesions and programmed DSBs, and many of the core DNA repair proteins function in both processes. In addition, DNA repair efficiency and crossover (CO) distribution are both influenced by local and global differences in chromatin structure, yet the interplay between chromatin structure, genome integrity, and meiotic fidelity is still poorly understood. We have used the xnd-1 mutant of Caenorhabditis elegans to explore the relationship between genome integrity and crossover formation. Known for its role in ensuring X chromosome CO formation and germ line development, we show that xnd-1 also regulates genome stability. xnd-1 mutants exhibited a mortal germ line, high embryonic lethality, high incidence of males, and sensitivity to ionizing radiation. We discovered that a hypomorphic allele of mys-1 suppressed these genome instability phenotypes of xnd-1, but did not suppress the CO defects, suggesting it serves as a separation-of-function allele. mys-1 encodes a histone acetyltransferase, whose homolog Tip60 acetylates H2AK5, a histone mark associated with transcriptional activation that is increased in xnd-1 mutant germ lines, raising the possibility that thresholds of H2AK5ac may differentially influence distinct germ line repair events. We also show that xnd-1 regulated him-5 transcriptionally, independently of mys-1, and that ectopic expression of him-5 suppressed the CO defects of xnd-1 Our work provides xnd-1 as a model in which to study the link between chromatin factors, gene expression, and genome stability.
Molecular Genetics and Developmental Biology Graduate Program, University of Pittsburgh School of Medicine, Pennsylvania.|Magee-Womens Research Institute, Department of Obstetrics, Gynecology, and Reproductive Services University of Pittsburgh School of Medicine, Pennsylvania 15213.
T Brooke
TB
McClendon
Magee-Womens Research Institute, Department of Obstetrics, Gynecology, and Reproductive Services University of Pittsburgh School of Medicine, Pennsylvania 15213.
Rana
R
Mainpal
Department of Pediatrics, University of Pittsburgh School of Medicine, Pennsylvania 15224.
Francis R G
FR
Amrit
Laboratory of Molecular Biology, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, Maryland 20892.
Michael W
MW
Krause
Department of Pediatrics, University of Pittsburgh School of Medicine, Pennsylvania 15224.
Arjumand
A
Ghazi
Molecular Genetics and Developmental Biology Graduate Program, University of Pittsburgh School of Medicine, Pennsylvania jly@alum.mit.edu.|Magee-Womens Research Institute, Department of Obstetrics, Gynecology, and Reproductive Services University of Pittsburgh School of Medicine, Pennsylvania 15213.
Judith L
JL
Yanowitz
D000483:Alleles; D000818:Animals; D030801:Animals, Genetically Modified; D017173:Caenorhabditis elegans / Q000235:genetics* / Q000378:metabolism; D029742:Caenorhabditis elegans Proteins / Q000235:genetics / Q000378:metabolism; D002843:Chromatin / Q000235:genetics* / Q000378:metabolism; D003434:Crossing Over, Genetic; D053903:DNA Breaks, Double-Stranded; D005298:Fertility / Q000235:genetics; D005786:Gene Expression Regulation; D042822:Genomic Instability; D005854:Germ Cells / Q000378:metabolism; D008540:Meiosis / Q000235:genetics; D009154:Mutation; D010641:Phenotype; D011839:Radiation, Ionizing; D019076:Transgenes; D014960:X Chromosome
D029742:Caenorhabditis elegans Proteins; D002843:Chromatin; C553799:xnd-1 protein, C elegans
ATM; Tip60; genome instability; ionizing radiation; meiosis
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