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Title: Meiotic interstrand DNA damage escapes paternal repair and causes chromosomal aberrations in the zygote by maternal misrepair

De novo point mutations and chromosomal structural aberrations (CSA) detected in offspring of unaffected parents show a preferential paternal origin with higher risk for older fathers. Studies in rodents suggest that heritable mutations transmitted from the father can arise from either paternal or maternal misrepair of damaged paternal DNA, and that the entire spermatogenic cycle can be at risk after mutagenic exposure. Understanding the susceptibility and mechanisms of transmission of paternal mutations is important in family planning after chemotherapy and donor selection for assisted reproduction. We report that treatment of male mice with melphalan (MLP), a bifunctional alkylating agent widely used in chemotherapy, induces DNA lesions during male mouse meiosis that persist unrepaired as germ cells progress through DNA repair-competent phases of spermatogenic development. After fertilization, unrepaired sperm DNA lesions are mis-repaired into CSA by the egg's DNA repair machinery producing chromosomally abnormal offspring. In conclusion, these findings highlight the importance of both pre- and post-fertilization DNA repair in assuring the genomic integrity of the conceptus.
Authors:
 [1] ;  [2] ;  [3] ;  [4]
  1. Environmental Health Science Research Bureau, Health Canada, Ottawa, ON (Canada); Lawrence Berkeley National Lab. (LBNL), Berkeley, CA (United States); Lawrence Livermore National Lab. (LLNL), Livermore, CA (United States)
  2. National Institute of Environmental Health Sciences, Research Triangle Park, NC (United States). National Toxicology Program
  3. Environmental Health Science Research Bureau, Health Canada, Ottawa, ON (Canada)
  4. Lawrence Berkeley National Lab. (LBNL), Berkeley, CA (United States); Lawrence Livermore National Lab. (LLNL), Livermore, CA (United States)
Publication Date:
OSTI Identifier:
1257269
Grant/Contract Number:
AC02-05CH11231; W-7405-END-48; Y01-ES-102-00
Type:
Accepted Manuscript
Journal Name:
Scientific Reports
Additional Journal Information:
Journal Volume: 5; Journal ID: ISSN 2045-2322
Publisher:
Nature Publishing Group
Research Org:
Lawrence Berkeley National Laboratory (LBNL), Berkeley, CA (United States)
Sponsoring Org:
USDOE
Country of Publication:
United States
Language:
English
Subject:
59 BASIC BIOLOGICAL SCIENCES cytogenetics; development