Microhomology directs diverse DNA break repair pathways and chromosomal translocations.
Microhomology directs diverse DNA break repair pathways and chromosomal translocations.
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DOI：
10.1371/journal.pgen.1003026
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发表时间：
2012
期刊：
影响因子：
4.5
通讯作者：
Lee SE
中科院分区：
文献类型：
--
作者：
Villarreal DD;Lee K;Deem A;Shim EY;Malkova A;Lee SE
染色体结构的改变会引发癌症和其他遗传性疾病的形成。这些重排的断点连接通常包含被称为“微同源”的小重叠序列，但负责的遗传途径(S)尚未确定。我们报道了一个简单的遗传系统来检测萌芽酵母细胞中DNA双链断裂(DSB)后的微同源介导的修复(MHMR)事件。MHMR使用>；15个碱基作为单链退火变异体，需要非必需的DNA聚合酶亚基Pol32。MHMR受到序列错配的抑制，但不依赖于广泛的DNA合成，如断裂诱导的复制。然而，使用少于14个碱基的MHMR与使用更长的微同源序列的MHMR在基因上是不同的，并且对于修复远距离的DSB来说效率要低得多。MHMR催化染色体易位的效率几乎与染色体内修复一样有效。结果表明，微同源序列之间的内在退火性有效地导致了染色体重排。癌症是由突变的积累造成的，这些突变将正常细胞转变为无法控制的增殖。DNA双链断裂(DSB)可导致基因突变和染色体重排，强调了功能性DNA DSB修复途径在维持染色体完整性和抑制肿瘤方面的重要性。大量证据表明，细胞具有多种具有不同突变潜能的DSB修复机制，其中一条或多条途径可能是染色体易位的形成原因。重要的是，在许多重排的交界处，发现了来自每个原始序列的小的(长度为2-20个碱基对)重叠序列，称为“微同源性”，它们可能提供关于这些重排如何形成的线索。在这里，我们描述了我们对侧翼微同源如何影响DSB修复的类型和频率的遗传学研究。我们还表明，微同源介导的修复(MHMR)有效地诱导了染色体易位。这项研究为利用微同源进行突变修复的机制提供了一个基本的理解。
Chromosomal structural change triggers carcinogenesis and the formation of other genetic diseases. The breakpoint junctions of these rearrangements often contain small overlapping sequences called “microhomology,” yet the genetic pathway(s) responsible have yet to be defined. We report a simple genetic system to detect microhomology-mediated repair (MHMR) events after a DNA double-strand break (DSB) in budding yeast cells. MHMR using >15 bp operates as a single-strand annealing variant, requiring the non-essential DNA polymerase subunit Pol32. MHMR is inhibited by sequence mismatches, but independent of extensive DNA synthesis like break-induced replication. However, MHMR using less than 14 bp is genetically distinct from that using longer microhomology and far less efficient for the repair of distant DSBs. MHMR catalyzes chromosomal translocation almost as efficiently as intra-chromosomal repair. The results suggest that the intrinsic annealing propensity between microhomology sequences efficiently leads to chromosomal rearrangements. Cancer results from an accumulation of mutations that transform a normal cell into one that proliferates uncontrollably. DNA double-strand breaks (DSBs) can lead to genetic mutations and chromosome rearrangements, underscoring the importance of functional DNA DSB repair pathways in the maintenance of chromosome integrity and tumor suppression. Ample evidence suggests that cells possess multiple DSB repair mechanisms with distinct mutational potentials, and one or more of these pathways is likely responsible for the formation of chromosomal translocations. Importantly, at the junctions of many rearrangements, small (2–20 bp in length) overlapping sequences from each of the original sequences, termed “microhomology,” are found, and they may provide a clue as to how these rearrangements form. Here, we describe our genetic investigation into how flanking microhomology influences the type and frequency of DSB repair. We also show that microhomology-mediated repair (MHMR) efficiently induces chromosomal translocations. This research provides a basic understanding of the mechanisms that utilize microhomology for mutagenic repair.
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影响因子：
56.9
作者：
FISHMANLOBELL, J;HABER, JE
通讯作者：
HABER, JE
影响因子：
16
作者：
Chen, C;Umezu, K;Kolodner, RD
通讯作者：
Kolodner, RD
DOI：
10.1126/science.1191125
发表时间：
2010-07-02
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Hicks WM;Kim M;Haber JE
通讯作者：
Haber JE
影响因子：
30.8
作者：
Campbell, Peter J.;Stephens, Philip J.;Pleasance, Erin D.;O'Meara, Sarah;Li, Heng;Santarius, Thomas;Stebbings, Lucy A.;Leroy, Catherine;Edkins, Sarah;Hardy, Claire;Teague, Jon W.;Menzies, Andrew;Goodhead, Ian;Turner, Daniel J.;Clee, Christopher M.;Quail, Michael A.;Cox, Antony;Brown, Clive;Durbin, Richard;Hurles, Matthew E.;Edwards, Paul A. W.;Bignell, Graham R.;Stratton, Michael R.;Futreal, P. Andrew
通讯作者：
Futreal, P. Andrew
影响因子：
5.3
作者：
Ira, G;Haber, JE
通讯作者：
Haber, JE