EVIDENCE FOR 2 SENESCENCE LOCI ON HUMAN-CHROMOSOME-I

Microcell-mediated introduction of a neo-tagged human chromosome 1 (HC -1-neo) into several immortal cell lines has previously been shown to induce growth arrest and phenotypic changes indicative of replicative senescence. Somatic cell hybridization studies have localized senescen ce activity for immortal hamster 10W-2 cells to a cytogenetically defi ned region between 1q23 and the q terminus. Previous microcell-mediate d chromosome transfer experiments showed that a chromosome 1 with an i nterstitial q-arm deletion (del-1q) lacks senescence inducing activity for several immortal human cell lines that are sensitive to an intact HC-1-neo. In contrast, our studies reveal that the del-1q chromosome retains activity for 10W-2 cells, indicating that there are at least t wo senescence genes on human chromosome 1. Sequence-tagged site (STS) content analysis revealed that the q arm of the del-1q chromosome has an interstitial deletion of approximately 63 centimorgans (cM), betwee n the proximal STS marker D1S534 and distal marker D1S412, approximate ly 1q12 to 1q31. This deletion analysis provides a candidate region fo r one of the senescence genes on 1q. In addition, because this deletio n region extends distally beyond 1q23, it localizes the region contain ing a second senescence gene to approximately 1q31-qter, between D1S42 2 and the q terminus. STS content analysis of a panel of 11 10W-2 micr ocell hybrid clones that escaped senescence identified 2 common region s of loss of 1q material below the distal breakpoint of del-1q. One re gion is flanked by markers D1S459 and ACTN2, and the second lies betwe en markers WI-4683 and D1S1609, indicating that the distal 1q senescen ce gene(s) localizes within 1q42-43. (C) 1996 Wiley-Liss, Inc