Mechanisms for recurrent and complex human genomic rearrangements

Liu, Pengfei; Carvalho, Claudia M.B.; Hastings, P. J.; Lupski, James R.

doi:10.1016/j.gde.2012.02.012

Cited by 311 publications

(339 citation statements)

References 76 publications

Supporting

Mentioning

310

Contrasting

Unclassified

Order By: Relevance

“…A particularly vexing problem in genome maintenance is the identification of mechanisms involved in gene duplications/amplifications and the mechanisms underlying complex genomic rearrangements causing massive genomic instability observed in some cancer cells, such as chromothrypsis (Hastings et al 2009;Liu et al 2011bLiu et al , 2012Forment et al 2012). …”

Section: Genome Maintenance and Human Diseasementioning

confidence: 99%

Regulation of Recombination and Genomic Maintenance

Heyer

2015

Cold Spring Harb Perspect Biol

104

View full text Add to dashboard Cite

Recombination is a central process to stably maintain and transmit a genome through somatic cell divisions and to new generations. Hence, recombination needs to be coordinated with other events occurring on the DNA template, such as DNA replication, transcription, and the specialized chromosomal functions at centromeres and telomeres. Moreover, regulation with respect to the cell-cycle stage is required as much as spatiotemporal coordination within the nuclear volume. These regulatory mechanisms impinge on the DNA substrate through modifications of the chromatin and directly on recombination proteins through a myriad of posttranslational modifications (PTMs) and additional mechanisms. Although recombination is primarily appreciated to maintain genomic stability, the process also contributes to gross chromosomal arrangements and copy-number changes. Hence, the recombination process itself requires quality control to ensure high fidelity and avoid genomic instability. Evidently, recombination and its regulatory processes have significant impact on human disease, specifically cancer and, possibly, neurodegenerative diseases.

show abstract

Section: Genome Maintenance and Human Diseasementioning

confidence: 99%

Regulation of Recombination and Genomic Maintenance

Heyer

2015

Cold Spring Harb Perspect Biol

104

View full text Add to dashboard Cite

show abstract

“…For example, segmental duplications .1 kb in size (88 to 99% identity, making up 5-10% of primate genomes) can serve as substrates for chromosomal rearrangements via NAHR (George and Alani 2012;Liu et al 2012). Heteroduplex rejection is likely to be a critical mechanism by which these NAHR events can be prevented.…”

Section: Relevance To Human Diseasementioning

confidence: 99%

“…For example, the organization of the interphase nucleus helps to limit physical interactions between distant regions of the genome, and cell cycle regulation of homologous recombination factors suppresses recombination events at times when distant genomic regions and nonallelic sequences tend to be unprotected or closer to each other (reviewed in George and Alani 2012). Despite these lines of defense, physical interactions between nonallelic sequences can still frequently occur, and when damage or replication stalling occurs in the vicinity of these interactions, nonallelic homologous recombination (NAHR) can be initiated (reviewed in Liu et al 2012). Several mechanisms have been proposed to understand how recombination events between divergent DNA sequences, known as homeologous recombination, are prevented.…”

mentioning

confidence: 99%

A Delicate Balance Between Repair and Replication Factors Regulates Recombination Between Divergent DNA Sequences inSaccharomyces cerevisiae

Chakraborty¹,

George²,

Lyndaker

et al. 2015

Genetics

View full text Add to dashboard Cite

Single-strand annealing (SSA) is an important homologous recombination mechanism that repairs DNA double strand breaks (DSBs) occurring between closely spaced repeat sequences. During SSA, the DSB is acted upon by exonucleases to reveal complementary sequences that anneal and are then repaired through tail clipping, DNA synthesis, and ligation steps. In baker's yeast, the Msh DNA mismatch recognition complex and the Sgs1 helicase act to suppress SSA between divergent sequences by binding to mismatches present in heteroduplex DNA intermediates and triggering a DNA unwinding mechanism known as heteroduplex rejection. Using baker's yeast as a model, we have identified new factors and regulatory steps in heteroduplex rejection during SSA. First we showed that Top3-Rmi1, a topoisomerase complex that interacts with Sgs1, is required for heteroduplex rejection. Second, we found that the replication processivity clamp proliferating cell nuclear antigen (PCNA) is dispensable for heteroduplex rejection, but is important for repairing mismatches formed during SSA. Third, we showed that modest overexpression of Msh6 results in a significant increase in heteroduplex rejection; this increase is due to a compromise in Msh2-Msh3 function required for the clipping of 39 tails. Thus 39 tail clipping during SSA is a critical regulatory step in the repair vs. rejection decision; rejection is favored before the 39 tails are clipped. Unexpectedly, Msh6 overexpression, through interactions with PCNA, disrupted heteroduplex rejection between divergent sequences in another recombination substrate. These observations illustrate the delicate balance that exists between repair and replication factors to optimize genome stability.

show abstract

“…Toutefois, il reste à apporter la preuve expérimentale de l'existence du chromothripsis, car comme le soulignent Liu et al [47], ainsi que Righolt et Mai [48], d'autres mécanismes peuvent aussi conduire à une accumulation graduelle des cassures chromosomiques, par exemple la fragilité particulière d'une région chromosomique. Le chromothripsis pourrait ne pas être un événement unique et isolé, mais faire partie d'un mécanisme plus complexe et dynamique de gestion de l'instabilité génomique.…”

Section: Resultsunclassified