Figure 1. Schematic representation of CDK9/CDK12 influence on DNA Damage Response. CDK9 interacts with cyclins T1/T2 and possibly also cyclin K. CDK12 binds cyclin K. Both kinase/cyclin complexes can phosphorylate RNA polymerase II C-terminal on Serine 2 (CTD S2ph). There seem to be at least 2 forms of Ser2 marks, possibly distinct in response to the action of the two kinases. CDK12 affects genomic stability through the regulation of gene expression of DNA damage responsive genes (ATR, BRCA1, FANCI). CDK9 can have direct and indirect effects on genomic stability. CDK9 can directly form a complex with ATR/ATRIP. Moreover, CDK9 phosphorylates CTD (which recruits E3 ligases -RNF20/40) and E2 (UBE2A) both required for H2B monoubiquitination (H2Bub1). This modification plays a critical role in chromatin structure modulation, potentially affecting the response to different damaging stresses: double strand breaks (DSB), DNA-RNA hybrid structures (R-loops), single strand breaks (SSB) and interstrand DNA crosslinks (ICLs). UBE2A phosphorylation can also directly affect SSB and ICLs.