Schematic diagram summarizing the cell-cycle and DNA damage response alterations in MCL, highlighting specific genomic copy number variations. The t(11;14)(q13;q32) translocation results in up-regulation of cyclin D1, an important regulator of the G1 phase of the cell cycle with its catalytic partner cyclin-dependent kinase 4 (CDK4). Overexpression of cyclin D1 maintains retinoblastoma (Rb) in a phosphorylated state leading to its inactivation and release of its suppression on the transcription factor E2F. E2F transactivates numerous S-phase gene promoters (cyclins D, E, A) and thus instigates DNA synthesis. Alterations described by Hartmann et al may act in the following ways. CUL4A binds to CDKN2A/p16 causing p16 activation. Loss of CUL4A prevents cell-cycle inhibition through p16. ING1 increases p21 expression by up-regulating the DNA damage-response gene p53. The loss of ING1 enhances cell-cycle progression through the G1/S checkpoint by removing the p21 brake. In MCL, MCPH1 is down-regulated resulting in increased cell cycling and a failure of apoptosis. Professional illustration by Debra T. Dartez.