| Functional module/process | ASCC2 molecular role | Key interacting partners | Subcellular localization | Key mechanistic details | Quantitative data | Key citations |
|---|---|---|---|---|---|---|
| DNA alkylation damage response | Ubiquitin-binding adaptor/sensor in the ALKBH3–ASCC repair pathway; recruits/helps recruit ASCC3 and ALKBH3 to alkylation-damage foci through its CUE domain (pqac-00000001, pqac-00000005, pqac-00000021) | ASCC3, ALKBH3, RNF113A-dependent K63-polyubiquitin, spliceosomal factors including BRR2/PRP8; broader ASCC complex includes ASCC1 and TRIP4/ASC1 (pqac-00000001, pqac-00000007, pqac-00000008, pqac-00000021, pqac-00000025) | Predominantly cytoplasmic at steady state, then accumulates in the nucleus and forms nuclear foci after alkylation stress; foci co-localize with K63-Ub, elongating RNA Pol II, and spliceosomal proteins (pqac-00000001, pqac-00000004, pqac-00000007) | ASCC2 CUE domain (aa ~465–521; UniProt domain annotation consistent) preferentially recognizes K63-linked polyubiquitin; N-terminal region of ASCC2 (aa 1–434) binds ASCC3 N-terminus, positioning ASCC3 to help generate ssDNA for ALKBH3 access to lesions such as N1-methyladenine and N3-methylcytosine during transcription-associated repair (pqac-00000003, pqac-00000005, pqac-00000006, pqac-00000016, pqac-00000021) | Kd: monoubiquitin 57.1 ± 5.0 μM; K63-Ub2 8.7–10.4 μM for isolated CUE and 8.8 ± 0.9 μM for full-length ASCC2; K48-Ub2 ~98 μM; linear diUb ~400 μM; E467A weakens binding 3.6–5.0× (Kd ~46.9–65.4 μM); S470R Kd ~90.9 ± 23.1 μM; E467R/S470R Kd ~92.6 ± 20.9 μM; ASCC2(1–434)-ASCC3(1–197) Kd 3.8 ± 1.2 nM; full-length ASCC2-ASCC3 NTR Kd 3.5 ± 0.4 nM (pqac-00000003, pqac-00000005, pqac-00000006, pqac-00000016, pqac-00000017, pqac-00000020) | Lombardi et al., 2022, *J Biol Chem*, https://doi.org/10.1016/j.jbc.2021.101545; Jia et al., 2020, *Nat Commun*, https://doi.org/10.1038/s41467-020-19221-x; Fahrer & Christmann, 2023, *Int J Mol Sci*, https://doi.org/10.3390/ijms24054684 (pqac-00000005, pqac-00000016, pqac-00000021) |
| Ribosome-associated quality control (RQC) / hRQT | Ubiquitin-recognition subunit of the mammalian hRQT/ASCC ribosome-splitting machinery; helps target ASCC3/TRIP4 to ubiquitinated stalled ribosomes (pqac-00000009, pqac-00000010, pqac-00000011) | ASCC3, TRIP4; upstream ZNF598-dependent K63-linked ubiquitination on small-subunit proteins (reported in Hashimoto for eS10; Miścicka shows ZNF598-dependent uS10/eS10 ubiquitination supports ASCC activity) (pqac-00000010, pqac-00000011, pqac-00000012) | Cytoplasmic/ribosome-associated functional context; acts on stalled 80S monosomes, polysomes, and even 48S complexes once appropriately ubiquitinated (pqac-00000009, pqac-00000012) | hRQT is composed of ASCC3-ASCC2-TRIP4; ASCC2 ubiquitin-binding activity is required/crucial for efficient RQC, while ASCC3 ATPase/helicase activity powers subunit dissociation. Recent reconstitution work shows ASCC can dissociate ubiquitinated ribosomal complexes without obligatory ribosome collision, provided ZNF598-dependent K63-linked ubiquitination and sufficient mRNA extension are present (pqac-00000009, pqac-00000010, pqac-00000011, pqac-00000012) | Functional KD evidence: ASCC3 KD abolishes RQC; ASCC2 KD partially impairs RQC; TRIP4 KD partially impairs RQC; ASCC1 not required (pqac-00000013). Miścicka 2024: ASCC can dissociate complexes with ≥30–35 nt 3' mRNA downstream of the P site; polysome stalling assays used 39 A residues/13 AAA Lys codons; ZNF598 generated near-complete eS10 and ~90% uS10 polyubiquitination with WT/K63-only Ub, whereas K63R Ub yielded only 1–4 Ub attachments (pqac-00000012, pqac-00000014) | Hashimoto et al., 2020, *Sci Rep*, https://doi.org/10.1038/s41598-020-60241-w; Miścicka et al., 2024, *Nucleic Acids Res*, https://doi.org/10.1093/nar/gkae087 (pqac-00000009, pqac-00000011, pqac-00000012, pqac-00000014) |
| ASCC2–ASCC3 structural module relevant to both pathways | High-affinity scaffold interface that physically links the ubiquitin-sensing ASCC2 subunit to the ASCC3 motor/helicase subunit, enabling downstream DNA-repair and ribosome-quality-control activities (pqac-00000015, pqac-00000016, pqac-00000017) | ASCC3 N-terminal region (especially first ~16 aa and broader 1–197/207 region); cancer-associated substitutions in both ASCC2 and ASCC3 map to the interface (pqac-00000016, pqac-00000018, pqac-00000019) | Applicable to nuclear DNA-damage complexes and cytoplasmic hRQT/ribosome complexes because the same ASCC2–ASCC3 core interaction is reused across functions (pqac-00000019) | ASCC2(1–434) forms a compact helical unit clasped by ASCC3(1–207); ASCC3 R5 and R11 contact acidic residues in ASCC2 (D103, D63, D92). The interface is evolutionarily conserved, and cancer mutations can weaken or abolish binding, suggesting disease-relevant destabilization of the core module (pqac-00000016, pqac-00000017, pqac-00000018) | ASCC3 minimal 1–22 peptide binds ASCC2(1–434) with Kd 2.0 μM; ASCC2(1–434)-ASCC3(1–161) Kd 47.7 ± 14.9 nM; truncation of ASCC3 N-terminus to aa 16–197 weakens to 483.0 ± 260.2 nM; deleting the N-arm abolishes detectable binding; ASCC3 R5L/G weaken affinity ~8–11×, R5H/C >20×, and R11H/C abolish binding (pqac-00000016, pqac-00000017, pqac-00000020) | Jia et al., 2020, *Nat Commun*, https://doi.org/10.1038/s41467-020-19221-x; Jia et al., 2023, *Nat Commun*, https://doi.org/10.1038/s41467-023-37528-3 (context mainly for ASCC3/TRIP4 module update) (pqac-00000015, pqac-00000016, pqac-00000017, pqac-00000020) |


*Table: This table summarizes the best-supported functional annotation for human ASCC2 across its two main mechanistic contexts: DNA alkylation repair and ribosome-associated quality control. It highlights domain function, partners, localization, mechanism, and quantitative measurements from primary studies, with 2023-2024 sources emphasized where available.*