Abstract
Inheriting a BRCA1 or BRCA2 gene mutation can cause a deficiency in repairing complex DNA damage. This step leads to genomic instability and probably contributes to an inherited predisposition to breast and ovarian cancer. Complex DNA damage has been viewed as an integral part of DNA replication before cell division. It causes temporary replication blocks, replication fork collapse, chromosome breaks and sister chromatid exchanges (SCEs). Chemical modification of DNA may also occur spontaneously as a byproduct of normal processes. Pathways containing BRCA1 and BRCA2 gene products are essential to repair spontaneous complex DNA damage or to carry out SCEs if repair is not possible. This scenario creates a theoretical limit that effectively means there are spontaneous BRCA1/2-associated cancers that cannot be prevented or delayed. However, much evidence for high rates of spontaneous DNA mutation is based on measuring SCEs by using bromodeoxyuridine (BrdU). Here we find that the routine use of BrdU has probably led to overestimating spontaneous DNA damage and SCEs because BrdU is itself a mutagen. Evidence based on spontaneous chromosome abnormalities and epidemiologic data indicates strong effects from exogenous mutagens and does not support the inevitability of cancer in all BRCA1/2 mutation carriers. We therefore remove a theoretical argument that has limited efforts to develop chemoprevention strategies to delay or prevent cancers in BRCA1/2 mutation carriers.
Highlights
Inheriting a BRCA1 or BRCA2 gene mutation can cause a dual deficiency both in repairing some complex DNA damage and in forming sister chromatid exchanges (SCEs) for damage that cannot be repaired
BRCA1/2 genes encode for proteins required for repairs that suppress some SCEs, and BRCA1/2 proteins are required for these crossover events [16]
Searches were expanded to include ATM or Fanconi proteins and SCE. This is justified because ATM and Fanconi gene (FA) products participate with BRCA1/2 proteins in a common pathway
Summary
Inheriting a BRCA1 or BRCA2 gene mutation can cause a dual deficiency both in repairing some complex DNA damage and in forming sister chromatid exchanges (SCEs) for damage that cannot be repaired. Any source of ongoing complex DNA damage places demands for normal BRCA1/2 gene products This scenario creates a theoretical limit that effectively means BRCA1/2-associated cancers occur spontaneously and cannot be prevented or delayed. Some DNA lesions have been viewed as an integral part of DNA replication before cell division [1], and they cause temporary replication blocks and replication fork collapse. This kind of replication stress can affect genomic loci such as fragile sites, telomeres and repetitive sequences [2]. Stalled and collapsed replication forks can lead to chromosome breaks and micronucleus formation They can trigger SCEs [3]. SCEs are widely believed to be a cytological manifestation of the repair of damaged or collapsed replication forks that occur all the time during DNA replication [4]
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