<p><span style="font-size: small">Telomeres, the protective elements at the ends of<br />chromosomes, need to be maintained for cells to<br />proliferate indefinitely. In many human cancers, the<br />telomeric DNA is replenished by telomerase. However, a<br />second pathway for telomere maintenance, referred to as<br />the ALT pathway, has increasingly been recognized in<br />human cancers. The genetic basis for activation of ALT is<br />not known, but recent data have implicated a chromatin<br />remodeling complex (ATRX/DAXX) and the histone variant<br />H3.3 as players in the repression of ALT. We have<br />examined a large panel of ALT cell lines for their genetic<br />and cell biological features and found that loss of ATRX is a<br />common event in the genesis of ALT lines. In addition, we<br />document that ALT cell lines frequently undergo chromosomal<br />changes and are impaired in their ability to detect<br />and repair damage in their DNA. These hallmarks of ALT<br />are expected to facilitate the detection of ALT–type tumors<br />in the clinic and may lead to ALT–specific treatments.</span></p>