突變通常被認(rèn)為是一個隨機的獨立的事件,。而近日發(fā)表在Molecular Cell的一項研究結(jié)果認(rèn)為酵母和人類腫瘤中的束狀突變（clustered mutation）不是隨機的，常發(fā)生在長單鏈DNA區(qū)域,。
對慢性烷基化損傷的酵母進(jìn)行測序發(fā)現(xiàn)束狀突變可達(dá)200kb,，而突變位點大多在雙鏈斷裂和復(fù)制叉處的長單鏈DNA,。
在已測序的人類腫瘤中也發(fā)現(xiàn)了相似的特征，突變的胞嘧啶和鳥嘌呤常常位于基因重組時的DNA鏈斷裂處,。APOBEC家族胞嘧啶脫氨酶的靶點大都為單鏈DNA,，其突變位點也異常豐富,。
結(jié)果表明,，同時發(fā)生的多種突變可以促進(jìn)腫瘤的發(fā)生,，也可促進(jìn)進(jìn)化。分析束狀突變也可為解開癌癥復(fù)雜的機制提供有效手段,。（生物谷Bioon.com）
doi:10.1016/j.molcel.2012.03.030
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PMID:
Clustered Mutations in Yeast and in Human Cancers Can Arise from Damaged Long Single-Strand DNA Regions
Steven A. Roberts, Joan Sterling, Cole Thompson, Shawn Harris, Deepak
Mav, Ruchir Shah, Leszek J. Klimczak, Gregory V. Kryukov, Ewa Malc, Piotr A. Mieczkowski, Michael A. Resnick, Dmitry A. Gordenin
Mutations are typically perceived as random, independent events. We describe here nonrandom clustered mutations in yeast and in human cancers. Genome sequencing of yeast grown under chronic alkylation damage identified mutation clusters that extend up to 200 kb. A predominance of “strand-coordinated” changes of either cytosines or guanines in the same strand, mutation patterns, and genetic controls indicated that simultaneous mutations were generated by base alkylation in abnormally long single-strand DNA (ssDNA) formed at double-strand breaks (DSBs) and replication forks. Significantly, we found mutation clusters with analogous features in sequenced human cancers. Strand-coordinated clusters of mutated cytosines or guanines often resided near chromosome rearrangement breakpoints and were highly enriched with a motif targeted by APOBEC family cytosine-deaminases, which strongly prefer ssDNA. These data indicate that hypermutation via multiple simultaneous changes in randomly formed ssDNA is a general phenomenon that may be an important mechanism producing rapid genetic variation.
