Genomic instability is a major driving force in the development of cancer. While genomic instability can have lethal consequences through the loss of essential genes, it increases the probability that cells acquire the multiple genetic alterations required for cancer to develop. Efforts to uncover the underlying mechanisms driving genomic instability in cancer have revealed a prominent role for telomeres. Telomeres are highly specialized, complex structures of DNA, RNA and proteins that cap chromosome ends and protect them from being recognized as DNA double-strand breaks. Loss of telomere protection leads to activation of DNA damage checkpoints and processing of deprotected chromosome ends by DNA repair factors that lead to chromosome-end fusions and dicentric chromosomes. If such cells with fused chromosomes continue to divide, this results in breakage-fusion-bridge cycles and complex, unbalanced chromosome rearrangements. However, the precise mechanisms by which dysfunctional telomeres lead to chromosomal instability and cancer are largely unknown. Using candidate-driven and genome-wide screening approaches, we have recently set out to identify the factors that play an important role in telomere-driven genome instability. One of the telomere-induced genome instability regulators we identified is WHSC1, also known as MMSET or NSD2. Alterations in WHSC1 are strongly associated with the Wolf-Hirschhorn malformation syndrome (WHS) and with multiple forms of cancer, especially multiple myeloma. In this proposal we will mechanistically investigate how WHSC1 controls telomere-driven genomic instability and whether this function might contribute to its role in cancer development. In addition, we will address the intriguing possibility that WHSC1 affects telomere maintenance.