TRF1 and TRF2 resolve replication stress and promote telomeric DNA replication. (a) TRF1 and TRF2 promote phosphorylation of BUB1, which recruits BLM to resolve G-quadruplex (G4) and RTEL1 to resolve the telomere loop (T-loop) to promote telomeric DNA replication. (b) TRF1 is PARylated by PARP1, and subsequently, the PARP1/TRF1 complex recruits BLM and WRN helicases to resolve G4 to promote telomeric DNA replication. (c) TRF1 recruits Timeless to telomeres, preventing replication fork stalling and facilitating telomere replication. (d) TRF2 inhibits the activation of ataxia telangiectasia-mutated (ATM) kinase and classical nonhomologous end joining(C-NHEJ) by sequestering the telomere end in the T-loop, thereby preventing the end-loading of the Mre11/Rad50/Nbs1 (MRN) complex and the Ku70/80 heterodimer. (e) TRF2 recruits TCOF1 to telomeres during the S phase to repress telomeric transcription and reduce replication stress by binding and inhibiting RNA Pol II.