Chromosome translocation in pre B cells: the role of an alternate DNA structure

描述(申请人提供)：近年来，替代DNA结构在染色体易位和其他重排中的作用引起了人们的注意。一种类型的替代结构，十字形，已被证明在体外形成组成回文的DNA序列。虽然强有力的证据表明人类的长回文DNA序列与可遗传的相互易位有关，但回文是否有助于生殖细胞以外的细胞易位尚未得到证实。这种可能性在T和B淋巴样细胞的情况下尤其相关，在分化过程中对准确的DNA新陈代谢有额外的要求，尽管易位是淋巴系统肿瘤的一个显著特征，但潜在的错误仅被部分定义。本研究的目的是测试(长)DNA回文可以在前/前B细胞中引发易位的概念。我们将研究小鼠PRO B细胞系(由Abelson鼠白血病病毒转化)和人类Pre-B系Nalm6的回文和易位之间的关系。将采用最近开发的一种在全基因组水平上描述易位的方法。这些研究可能会建立一种新的内源性DNA损伤类别，对淋巴系统内外的肿瘤发生和其他病理学具有重要意义。 与公共健康相关：作用于DNA以复制、转录、重组或修饰分子的酶都能识别特定的结构。某些DNA序列有局部异常构象的倾向，这带来了被DNA酶不当操作的风险。本提案旨在分析一种特殊的DNA序列基序(一种没有中心间隔区的反向重复序列)，它有可能形成分枝的“十字形”结构，以研究其在细胞中引发染色体易位的能力。

DESCRIPTION (provided by applicant): The involvement of alternative DNA structures in chromosome translocations and other rearrangements has gained attention in recent years. One type of alternative structure, a cruciform, has been demonstrated to form at DNA sequences that comprise a palindrome in vitro. While strong evidence causally implicates long palindromic DNA sequences with heritable reciprocal translocations in humans, whether palindromes contribute to translocation in cells other than germ cells has not been demonstrated. The possibility is particularly relevant in the case of T and B lymphoid cells where there are extra demands placed upon accurate DNA metabolism during differentiation, and where, although translocation is a marked feature in tumors of the lymphoid system, the underlying errors have been only partially defined. The purpose of the present study is to test the notion that (long) DNA palindromes can instigate translocation in pro/pre B cells. The relationship between palindromy and translocation in mouse pro B cell lines (transformed by Abelson murine leukemia virus), and in a human pre-B line, Nalm6, will be investigated. A recently developed method for characterizing translocation at a genome-wide level will be employed. These studies may establish a new category of endogenously generated DNA damage with significance in tumorigenesis and other pathologies in the lymphoid system and beyond. PUBLIC HEALTH RELEVANCE: Enzymes that work on DNA in order to replicate, transcribe, recombine or modify the molecule all recognize specific structures. Certain DNA sequences have a tendency to assume locally abnormal conformations, and these pose the risk of being improperly manipulated by DNA enzymes. The present proposal is aimed at analyzing a particular DNA sequence motif (an inverted repeat sequence with no central spacer) that has a tendency to form branched 'cruciform' structures, for its ability to instigate chromosomal translocations in cells.