Abstract
Understanding the mitotic DNA damage response (DDR) is critical to our comprehension of cancer, premature aging and developmental disorders which are marked by DNA repair deficiencies. In this study we use a micro-focused laser to induce DNA damage in selected mitotic chromosomes to study the subsequent repair response. Our findings demonstrate that (1) mitotic cells are capable of DNA repair as evidenced by DNA synthesis at damage sites, (2) Repair is attenuated when DNA-PKcs and ATM are simultaneously compromised, (3) Laser damage may permit the observation of previously undetected DDR proteins when damage is elicited by other methods in mitosis, and (4) Twenty five percent of mitotic DNA-damaged cells undergo a subsequent mitosis. Together these findings suggest that mitotic DDR is more complex than previously thought and may involve factors from multiple repair pathways that are better understood in interphase.
Highlights
PKcsi DNA PKcs Inhibitor (DNA) damage occurs naturally through various endogenous and exogenous processes
Our results indicate that double strand break (DSB) generated on metaphase chromosomes lead to clustering of various proteins involved in non-homologous end joining (NHEJ) and homologous recombination (HR)
We detected the recruitment of factors involved in different DNA repair pathways, including DSB and single-strand breaks (SSBs) repair, base excision repair (BER) and nucleotide excision repair (NER), Fig 11B
Summary
DNA damage occurs naturally through various endogenous and exogenous processes. Unrepaired DNA can compromise genetic integrity leading to developmental disorders, cell death or cancer. Organisms have evolved a variety of pathways to respond to the damage. The vast majority of studies on DNA damage responses have been done during interphase of the cell cycle. Understanding the DNA damage response (DDR) during mitosis is important since mutations accumulated during mitosis can lead to chromosomal aberrations, genomic instability of daughter cells, senescence and eventual cell death [1,2,3,4]. Studies examining the extent of DDR activation and repair in mitosis have primarily assessed the cellular response to double strand breaks (DSBs). DSBs may be repaired by homologous recombination (HR) and non-homologous end joining (NHEJ).
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