Alu elements and DNA double-strand break repair

White, Travis B.; Morales, Maria E.; Deininger, Prescott L.

doi:10.1080/2159256x.2015.1093067

Cited by 18 publications

(18 citation statements)

References 27 publications

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“…A schematic of both types of outcomes is shown in Fig 4 . We previously showed that complex chimera arise from the RAD52-dependent annealing of the strands from the two diverged Alu elements that have escaped heteroduplex rejection and seem likely to be due to SSA [ 24 ], while the simple chimera are likely to be the result of alt-NHEJ where the microhomologies are ‘in-register’ within the Alu elements [ 35 ]. Such an annealed SSA-like product would be a substrate for mismatch repair processes, which is suggested to produce an Alu element containing patches from each Alu element i .…”

Section: Resultsmentioning

confidence: 99%

Heavy Metal Exposure Influences Double Strand Break DNA Repair Outcomes

et al. 2016

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Heavy metals such as cadmium, arsenic and nickel are classified as carcinogens. Although the precise mechanism of carcinogenesis is undefined, heavy metal exposure can contribute to genetic damage by inducing double strand breaks (DSBs) as well as inhibiting critical proteins from different DNA repair pathways. Here we take advantage of two previously published culture assay systems developed to address mechanistic aspects of DNA repair to evaluate the effects of heavy metal exposures on competing DNA repair outcomes. Our results demonstrate that exposure to heavy metals significantly alters how cells repair double strand breaks. The effects observed are both specific to the particular metal and dose dependent. Low doses of NiCl2 favored resolution of DSBs through homologous recombination (HR) and single strand annealing (SSA), which were inhibited by higher NiCl2 doses. In contrast, cells exposed to arsenic trioxide preferentially repaired using the “error prone” non-homologous end joining (alt-NHEJ) while inhibiting repair by HR. In addition, we determined that low doses of nickel and cadmium contributed to an increase in mutagenic recombination-mediated by Alu elements, the most numerous family of repetitive elements in humans. Sequence verification confirmed that the majority of the genetic deletions were the result of Alu-mediated non-allelic recombination events that predominantly arose from repair by SSA. All heavy metals showed a shift in the outcomes of alt-NHEJ repair with a significant increase of non-templated sequence insertions at the DSB repair site. Our data suggest that exposure to heavy metals will alter the choice of DNA repair pathway changing the genetic outcome of DSBs repair.

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Section: Resultsmentioning

confidence: 99%

Heavy Metal Exposure Influences Double Strand Break DNA Repair Outcomes

et al. 2016

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“…1A). The size of the repeat was chosen to approximate the length of Alu elements, which are between 280 and 300 bp (Batzer and Deininger 2002;White et al 2015). The 5 ′ repeat is a segment of exon 2 of the Cdkn1A gene.…”

Section: Influence Of Dsb/repeat Distance On Rmd Frequencymentioning

confidence: 99%

“…The Alu elements associated with RMDs can be separated by very short distances (such as <1 kb) or span a large fraction of a gene (e.g., >20 kb and encompassing several exons) (Kolomietz et al 2002;Pavlicek et al 2004;Belancio et al 2010). Furthermore, sequence divergence between Alu elements can range between 0% and 30%, depending on the family/subfamily of the pair of repeats (Batzer and Deininger 2002;White et al 2015). Thus, defining the influence of interrepeat distance and repeat divergence on RMDs as well as the DNA repair pathways that influence these variables will provide insight into the etiology of this class of SVs.…”

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confidence: 99%

Repeat-mediated deletions can be induced by a chromosomal break far from a repeat, but multiple pathways suppress such rearrangements

2018

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Chromosomal deletion rearrangements mediated by repetitive elements often involve repeats separated by several kilobases and sequences that are divergent. While such rearrangements are likely induced by DNA double-strand breaks (DSBs), it has been unclear how the proximity of DSBs relative to repeat sequences affects the frequency of such events. We generated a reporter assay in mouse cells for a deletion rearrangement involving repeats separated by 0.4 Mb. We induced this repeat-mediated deletion (RMD) rearrangement with two DSBs: the 5' DSB that is just downstream from the first repeat and the 3' DSB that is varying distances upstream of the second repeat. Strikingly, we found that increasing the 3' DSB/repeat distance from 3.3 kb to 28.4 kb causes only a modest decrease in rearrangement frequency. We also found that RMDs are suppressed by KU70 and RAD51 and promoted by RAD52, CtIP, and BRCA1. In addition, we found that 1%-3% sequence divergence substantially suppresses these rearrangements in a manner dependent on the mismatch repair factor MSH2, which is dominant over the suppressive role of KU70. We suggest that a DSB far from a repeat can stimulate repeat-mediated rearrangements, but multiple pathways suppress these events.

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“…In the human genome, most repetitive sequences such as Alu elements are not identical (Batzer & Deininger, 2002;White et al, 2015). To examine the role of BIR in RMD between divergent repeat sequences, we used previously established RMD-GFP reporters that contain 1% or 3% divergence in repeats (Mendez-Dorantes et al, 2018).…”

Section: Divergence In Repeat Sequences Strongly Inhibits Bir/rmd Parmentioning

confidence: 99%

Break‐induced replication plays a prominent role in long‐range repeat‐mediated deletion

Lü

Wang

et al. 2019

The EMBO Journal

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Repetitive DNA sequences are often associated with chromosomal rearrangements in cancers. Conventionally, single‐strand annealing (SSA) is thought to mediate homology‐directed repair of double‐strand breaks (DSBs) between two repeats, causing repeat‐mediated deletion (RMD). In this report, we demonstrate that break‐induced replication (BIR) is used predominantly over SSA in mammalian cells for mediating RMD, especially when repeats are far apart. We show that SSA becomes inefficient in mammalian cells when the distance between the DSBs and the repeats is increased to the 1–2 kb range, while BIR‐mediated RMD (BIR/RMD) can act over a long distance (e.g., ~ 100–200 kb) when the DSB is close to one repeat. Importantly, oncogene expression potentiates BIR/RMD but not SSA, and BIR/RMD is used more frequently at single‐ended DSBs formed at collapsed replication forks than at double‐ended DSBs. In contrast to short‐range SSA, H2AX is required for long‐range BIR/RMD, and sequence divergence strongly suppresses BIR/RMD in a manner partially dependent on MSH2. Our finding that BIR/RMD has a more important role than SSA in mammalian cells has a significant impact on the understanding of repeat‐mediated rearrangements associated with oncogenesis.

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Alu elements and DNA double-strand break repair

Cited by 18 publications

References 27 publications

Heavy Metal Exposure Influences Double Strand Break DNA Repair Outcomes

Heavy Metal Exposure Influences Double Strand Break DNA Repair Outcomes

Repeat-mediated deletions can be induced by a chromosomal break far from a repeat, but multiple pathways suppress such rearrangements

Break‐induced replication plays a prominent role in long‐range repeat‐mediated deletion

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