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Translesion (TLS) polymerases rescue stalled DNA polymerases at sites of damaged bases by replacing the replicative polymerase and installing a nucleotide across the damaged site. Doing so, TLS allows additional time for the cell to repair the damage before resuming regular DNA replication.

TLS polymerases are found in all three domains of life - archaea, bacteria, and eukaryotes. Of the different classes of TLS polymerases, members of the Y family are fitted with specialized structures that are optimized to carry out TLS DNA synthesis.

Despite sharing structural similarities, Y family polymerases differ from replicative polymerases in certain key ways that allow them to perform TLS. Y family polymerases lack the intrinsic 3′-to-5′ exonuclease domain of replicative DNA polymerases that allows them to proofread the newly replicated strand. Another key difference is the larger and more open active site of Y family TLS polymerases that can fit bulky, chemically modified bases, including covalently linked bases in a thymine-thymine dimer.

During TLS DNA synthesis, TLS polymerase must extend the strand beyond the insertion across the damaged site. If the replicative polymerase is reinstated right after the TLS polymerase inserts a base, the 3’ to 5’ exonuclease proofreading activity of the replicative polymerase will recognize and remove the inserted base. The length of extension by the TLS polymerase depends on the pathway followed. For a non-mutagenic pathway, the number of insertion maybe 5, while for a frameshift pathway, the insertion will be 4 nucleotides-long.

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