Although small in size (~35 kb), the INK4/ARF locus is a critically important regulator of cancer and aging. Two genes within the locus, CDKN2A and CDKN2B, encode for three distinct proteinsp15INK4b, p16INK4a and ARF (Fig. 1). All three proteins function to prevent cancer, acting through either the retinoblastoma or p53 tumor suppressor pathways. Patients with germline losses of the INK4/ARF locus are highly susceptible to cancer, and many tumors silence the locus somatically via methylation, deletion or mutation. Persistent expression of p16INK4a can drive cells to enter an irreversible cell cycle state known as cellular senescence. As we age, it is believed that our bodies accumulate senescent cells, reducing our ability to regenerate tissues and promoting a wide variety of age-related diseases (e.g. diabetes, frailty). Therefore, regulation of the INK4/ARF locus must be tightly controlled to prevent cancer without promoting decline
