{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nDNA polymerase μ (POLM) is a versatile X‐family enzyme that plays a pivotal role in double‐strand break repair via nonhomologous end joining (NHEJ). Upon DNA damage such as ionizing radiation, POLM is upregulated and rapidly recruited to damaged sites—forming nuclear foci that colocalize with γH2AX—and interacts with core NHEJ factors (for example, Ku and XRCC4–ligase IV) to catalyze gap‐filling reactions even when DNA ends display limited complementarity. This specialized activity is particularly important during V(D)J recombination, where its unique capacity to add nucleotides contributes to the accuracy of immunoglobulin gene rearrangements."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "4"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nBiochemical and structural studies reveal that POLM operates in dual modes: it can perform template‐dependent DNA synthesis with high efficiency or act in a terminal transferase–like manner in the absence of base pairing. Early investigations demonstrated unusual primer extension activity even across adducted templates"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "5"}]}, {"type": "t", "text": ", and subsequent analyses showed that POLM efficiently bypasses common lesions—including abasic sites, bulky DNA adducts, and cis–syn thymine dimers—often using a misalignment or deletion mechanism."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "6"}]}, {"type": "t", "text": " Moreover, POLM exhibits a considerably relaxed sugar selectivity, readily incorporating ribonucleotides under physiological nucleotide pool conditions"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "7"}]}, {"type": "t", "text": ", and displays a dual polymerization activity as evidenced by its template‐dependent and template–independent synthesis."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "8"}]}, {"type": "t", "text": " Key structural elements—including a flexible “loop1” that can adopt alternate conformations to either mimic a pseudotemplate or allow normal templating, as well as a conserved “brooch” sequence—are essential for mediating these functional switches."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "9", "end_ref": "14"}]}, {"type": "t", "text": " High-resolution structures of its catalytic cycle further illustrate that POLM does not require the extensive conformational rearrangements typical of other template–dependent polymerases, and that repositioning of loop1 is critical for aligning unpaired 3′ ends during gap filling."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "15", "end_ref": "17"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nIn vivo, POLM is highly expressed in lymphoid tissues where its error–prone, misincorporation–prone activity contributes both to somatic hypermutation in immunoglobulin genes and to the generation of genetic diversity; however, such mutagenic potential can also lead to genomic instability. Importantly, post–translational control—such as Cdk–mediated phosphorylation that targets residues influencing loop1 mobility—modulates its balance between template–dependent synthesis and terminal transferase activity, while point mutations identified in tumors further underscore its dual role in precise DNA repair and in error–prone gap filling during NHEJ."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "18", "end_ref": "22"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Kiran N Mahajan, Stephanie A Nick McElhinny, Beverly S Mitchell, et al. 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