The replicative polymerase delta is inefficient copying repetitive DNA sequences. Error-prone translesion polymerases have been shown to switch with high-fidelity replicative polymerases to help navigate repetitive DNA. We and others have demonstrated the importance of one such translesion polymerase, polymerase Eta (pol eta), in facilitating replication at genomic regions called common fragile sites (CFS), which are difficult-to-replicate genomic regions that are hypersensitive to replication stress. However, the mechanistic basis for pol eta's role in facilitating DNA replication at CFS and(or) at other genomic regions is currently unclear. Importantly, the functional importance of three non-catalytic domains of pol eta, the Ubiquitin-binding Zinc finger (UBZ), PCNA interacting protein (PIP) domain, and the F1 domain which mediates its switch with replicative DNA polymerases in mediating replication stress, especially at CFS loci is not clear. Here, we report that the PIP and UBZ domains of Pol Eta are both critical for its role in mediating cellular replication stress, especially at CFS. The absence of either domain induced elevated replication stress, replication stalling and DNA damage accumulation genome wide. This effect was even more pronounced at CFS loci leading to the accumulation of under replication DNA in G2/M. Importantly, while the inactivation of the UBZ domain resulted in a robust FANCD2 monoubiquitylation (a prominent marker of FANCD2 activation), FANCD2 recruitment genome wide was significantly impacted, especially at CFSs such as FRA16D. These S-phase phenotypes result in ssDNA gap formation and the persistence of under-replicated genomic regions upon transition to G2/M. While post-replicative gap filing/ repair by Mitotic DNA synthesis is activated in the mutants, it only effectively resolves UFBs in the F1* cells. The PIP*, UBZ* and pol eta -/- cells unfortunately manifest excessive toxic cytosolic DNA that instigates a strong innate immune response. These results collectively show that translesion polymerase Eta functions in a common pathway with FANCD2 to prevent replication perturbation and instability at CFS loci.